Pyrrolo[2,3-d]pyrimidine cytokine inhibitors

ABSTRACT

The present invention relates to 2,6,7-substituted pyrrolo[2,3-d]pyrimidines which inhibit the extracellular release of inflammatory cytokines, said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said 2,6,7-substituted pyrrolo[2,3-d]pyrimidines and methods for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority under Title 35, United States Code 119(e) from Provisional Application Ser. No. 60/527,967, filed Dec. 9, 2003.

FIELD OF THE INVENTION

The present invention relates to 2,6,7-substituted pyrrolo[2,3-d]pyrimidines which inhibit the extracellular release of inflammatory cytokines, compositions comprising said 2,6,7-substituted pyrrolo[2,3-d]pyrimidines and methods for preventing, abating, or otherwise controlling the extracellular release of inflammatory cytokines.

DETAILED DESCRIPTION OF THE INVENTION

It has been surprisingly found that certain pyrrolo[2,3-d]pyrimidines, inter alia, 2-heterocycloamino-6-[substituted or unsubstituted]acyl-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines, 2-aryloxy-6-[substituted or unsubstituted]acyl-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines, or 2-[substituted or unsubstituted]alkylamino-6-[substituted or unsubstituted]acyl-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines, and derivatives thereof are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states.

The present invention relates to pyrrolo[2,3-d]pyrimidines, for example, 2-heterocycloamino-6-[substituted or unsubstituted]acyl-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines are suitable for mediating, controlling or otherwise inhibiting the extracellular release of certain cytokines, especially inflammatory cytokines, said cytokines playing a role in the stimulation, cause or manifestation of a wide variety of diseases, disease states, or syndromes.

The following chemical hierarchy is used throughout the specification to particularly point out and distinctly claim the units which comprise the compounds of the present invention. The term “hydrocarbyl” stands for any organic molecule, organic functional group, including inorganic atom comprising salts, inter alia, carboxylate salts, quaternary ammonium salts, or for any portion, unit, moiety, and the like, of an organic molecule. Encompassed within the term “hydrocarbyl” are the terms “acyclic” and “cyclic” units which divide hydrocarbyl into cyclic and non-cyclic classes. Acyclic units include alkyl, alkenyl, alkynyl units and their corresponding connecting units, inter alia, alkylene, all of which can be substituted by the suitable substitutions for hydrogen defined herein. Encompassed within the term “cyclic hydrocarbyl” are the carbocyclic, heterocyclic, aryl, and heteroaryl units, and their corresponding connecting units, inter alia, arylene, all of which can be substituted by the suitable substitutions for hydrogen defined herein. Included within the carbocyclic definition are spirocyclic rings, bicyclic rings, and bridged bicyclic rings, as well as fused rings, inter alia, tetralin. For the purposed of the present invention fused ring units which comprise a single heteroatom within a non-aromatic ring, for example, 1,2,3,4-tetrahydroquinoline having the formula:

is considered a heterocyclic ring, while 6,7-dihydro-5H-[1] pyridine having the formula:

is considered a heteroaryl unit since the heteroatom comprises an aromatic ring.

Included within the definition of “hydrocarbyl” as defined herein above, are the aromatic (aryl) and non-aromatic (carbocyclic) rings, non-limiting examples of which include cyclopropyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cyclohexenyl, cycloheptanyl, bicyclo-[0.1.1]-butanyl, bicyclo-[0.1.2]-pentanyl, bicyclo-[0.1.3]-hexanyl (thujanyl), bicyclo-[0.2.2]-hexanyl, bicyclo-[0.1.4]-heptanyl (caranyl), bicyclo-[2.2.1]-heptanyl(norboranyl), bicyclo-[0.2.4]-octanyl(caryophyllenyl), spiropentanyl, diclyclopentanespiranyl, decalinyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthryl, fluorenyl, acenaphthylenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.

Included within the definition of “hydrocarbyl” as defined herein above, are the heteroatom-comprising aromatic (heteroaryl) and non-aromatic (heterocyclic) rings, non-limiting examples of which include: pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazoyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1,2-diazepinyl, indenyl 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, furanyl, thiophenyl, benzimidazolyl, and the like each of which can be substituted or unsubstituted.

The term “aryloyl” as it relates to units attached to the core pyrrolo[2,3-d]pyrimidine scaffold further defined herein below. A non limiting example of an aryloyl substituent is a substituted or unsubstituted benzoyl unit having the general formula:

wherein R^(a) represents one or more possible substitutions for a hydrogen atom.

The term “substituted” is used throughout the specification. The term “substituted” is defined herein as “a hydrocarbyl moiety, whether acyclic or cyclic, which has one or more hydrogen atoms replaced by a substituent or several substituents as defined herein below. The units, which substituted for hydrogen atoms are capable of replacing one hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety at a time. In addition, these substituents can replace two hydrogen atoms on two adjacent carbons to form said substituent, new moiety or unit.” For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. A two hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Three hydrogen replacement includes cyano, and the like. The term substituted is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a moiety is described as “substituted” any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a “substituted aromatic carbocyclic ring”, (N,N-dimethyl-5-amino)octanyl is a “substituted C₈ alkyl unit, 3-guanidinopropyl is a “substituted C₃ alkyl unit,” and 2-carboxypyridinyl is a “substituted heteroaryl unit.”

The following are non-limiting examples of units which can substitute for hydrogen atoms on a hydrocarbyl or other unit:

i) —OR¹²;

ii) —C(O)R¹²

iii) —C(O)OR¹²

iv) —C(O)N(R¹²)₂;

v) —CN;

vi) —N(R¹²)₂;

vii) -halogen; and

viii) —CF₃, —CCl₃, —CBr₃;

wherein R¹² is hydrogen, substituted or unsubstituted C₁-C₄ linear, branched, or cyclic alkyl, and mixtures thereof.

The compounds of the present invention are pyrrolo[2,3-d]pyrimidines having the core scaffold:

wherein the numbered positions on the ring relate to the naming and substitutions at each position described herein.

R units which comprise the compounds of the present invention are chosen from:

i) substituted or unsubstituted C₆-C₁₀ aryl;

ii) substituted or unsubstituted C₁-C₆ linear or branched acyclic hydrocarbyl;

iii) substituted or unsubstituted C₁-C₁₀ heterocyclic; and

iv) substituted or unsubstituted C₁-C₁₀ heteroaryl.

The first aspect of R units relates to substituted or unsubstituted C₆-C₁₀ aryl units, that is aryl units comprising from 6 to 10 carbon atoms, wherein said substitution is chosen from: halogen, C₁-C₄ linear or branched alkyl, —OH, —OR⁸, —CN, —N(R⁸)₂, —CO₂R⁸, —CON(R⁸)₂, —NR⁸COR⁸, and —NO₂; each R⁸ is independently hydrogen, C₁-C₄ alkyl, or two R⁸ units can be taken together to form a ring comprising from 3-7 atoms.

The first iteration of this aspect encompasses units chosen from: phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, and 2,6-dichlorophenyl.

A second iteration of this aspect relates to aryl units substituted with a unit chosen from:

i) —CO₂R^(8;),

ii) —CON(R⁸)₂; and

iii) —NR⁸COR⁸;

wherein R⁸ is hydrogen, methyl, or ethyl

The third iteration of this aspect relates to aryl units chosen from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxy-phenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, and 2,6-dimethoxyphenyl.

The second aspect of R units relates to substituted or unsubstituted 5-member ring C₁-C₄ heterocyclic units, that is heterocyclic units comprising from 1 to 4 carbon atoms. The first iteration of this aspect encompasses units chosen from pyrrolidin-1-yl, pyrrolidin-4-yl, tetrahydrofuran-2-yl, imidazolidin-2-yl, and imidazolidin-4-yl.

The third aspect of R units relates to substituted or unsubstituted 6-member ring C₁-C₅ heterocyclic units, that is heterocyclic units comprising from 1 to 5 carbon atoms. The first iteration of this aspect encompasses units chosen from piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, and pyran-4-yl.

The fourth aspect of R units relates to substituted or unsubstituted C₁-C₆ linear or branched alkyl unit having the formula:

wherein R⁹, R^(10a), R^(10b), and R¹¹ are each independently; i) hydrogen; ii) C₁-C₄ alkyl; iii) —OH; or iv) C₁-C₄ alkoxy.

A first iteration of this aspect includes chiral R units, for example, units having the formula:

Non-limiting examples of other R units which are encompassed by this iteration include units chosen from 2-methyl-2-hydroxy-1-(S)-methylpropyl, 2-methoxy-1-(S)-methylethyl, 2-methyl-2-cyano-1-(S)-methylpropyl, 2-methyl-2-hydroxy-1-(R)-methylpropyl, 2-methoxy-1-(R)-methylethyl, 2-methyl-2-cyano-1-(R)-methylpropyl, 1-(S)-methylpropyl, and 1-(R)-methylpropyl.

Another iteration includes the racemic mixtures of substituted and unsubstituted C₁-C₆ alkyl units, for example, units chosen from 1,2-dimethyl-2-hydroxypropyl, 2-methoxy-1-methylethyl, 1,2-dimethyl-2-cyanopropyl, and 1-methylpropyl.

The fifth aspect of R relates to R units which are amino units. The first iteration of this aspect relates to R amino units which are taken together with L units described herein below which comprise a —NH— moiety. Therefore when R and L are taken together they represent hydrazine units, for example, (CH₃)₂NNH—, (CH₃CH₂)₂NNH—, C₅H₁₀NNH— (piperidin-1-ylamino), and (C₄H₈ON)NH— (morpholin-4-ylamino) as described further herein below.

R¹ is chosen from:

i) hydrogen; and

ii) substituted or unsubstituted C₆-C₁₀ aryl.

The first aspect of R¹ relates to C₆ aryl units chosen from phenyl, 2-chlorphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, and 2,6-dimethylphenyl.

R² is substituted or unsubstituted C₆-C₁₀ aryl.

The first aspect of R² relates to C₆ aryl units chosen from phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,5-dichlorophenyl, and 2,6-dichlorophenyl.

The second aspect of R² relates to C₆ aryl units chosen from 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxy-phenyl, 2,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, and 2,6-dimethoxyphenyl.

L and L¹ are linking units each of which independently has the formula:

Z, Z¹, and Z² are each independently a unit chosen from:

i) —NR⁵—;

ii) —O—;

iii) —C(O)—;

iv) —CHOR⁵—;

v) —SO₂—;

vi) —NR⁵SO₂—; and

vii) —SO₂NR⁵—;

each of the indices j is independently 0 or 1. Each R⁵ unit is independently chosen from:

i) hydrogen;

ii) substituted or unsubstituted C₁-C₄ linear, branched, or cyclic alkyl;

iii) —COR⁶;

iv) —[C(R⁶)₂]_(x)CO₂R⁶; or

v) —[C(R⁶)₂]_(x)CON(R⁶)₂;

R⁶ is hydrogen, C₁-C₄ substituted or unsubstituted alkyl, or two R⁶ units on adjacent carbon atoms can be taken to form a double bond;

R^(3a), R^(3b), R^(4a), and R^(4b) are each independently:

-   -   i) hydrogen;     -   ii) —OR⁶;     -   iii) halogen;     -   iv) —[C(R⁶)₂]_(x)CO₂R⁶; or     -   v) —[C(R⁶)₂]_(x)CON(R⁶)₂;     -   vi) C₁-C₄ linear, branched, or cyclic alkyl;     -   vii) halogen substituted C₁-C₄ linear, branched, or cyclic         alkyl;     -   viii) C₁-C₄ linear, branched, or cyclic alkoxy;     -   ix) R^(3a) and R^(3b) or R^(4a) and R^(4b) can be taken together         to form a unit having the formula: C═X wherein X is O, S, NR⁵,         or NOR⁷; R⁷ is hydrogen, C₁-C₄ linear alkyl, and —COR⁶;     -   x) two R^(3b) or two R^(4b) units from adjacent carbon atoms can         be taken together to form a double bond;     -   xi) R^(3a) and R^(3b) or R^(4a) and R^(4b) can be taken together         to form a ring comprising from 3 to 7 atoms; and     -   xii) R^(3a) and R^(3b) or R^(4a) and R^(4b) can be taken         together to form a unit chosen from ═CH[C(R⁶)₂]_(x)CO₂R⁶,         ═CH[C(R⁶)₂]_(x)CON(R⁶)₂, and ═CH[C(R⁶)₂]_(x)OC(O)R⁶;         the indices m and n are each independently from 0 to 5; x is         from 0 to 5.

The first aspect of linking groups relates to compounds wherein L and L¹ are each independently chosen from:

i) —NH—;

ii) —O—;

iii) —SO₂—;

iv) —C(O)—;

v) —C═NOR⁶;

vi) —C(R⁶)₂—;

vii) —C[═C(R⁶)₂]-; and

viii) —C(OR⁵)₂—;

wherein R⁵ is hydrogen, —COR⁶, or two R⁵ units can be taken together with the oxygen atoms to form a cyclic ketal ring comprising 5 or 6 atoms; R⁶ is methyl, ethyl, or n-propyl.

A second aspect of linking group relates to compound having the formula:

wherein L¹ is a carbonyl unit as depicted herein above and L is —NH— or —O—.

Another aspect of linking units relates to L¹ units which comprise R^(3a) and R^(3b) or R^(4a) and R^(4b) units which can be taken together to form a unit having the formula: C═X wherein X is NOR⁷; R⁷ is hydrogen, C₁-C₄ linear alkyl, and —COR⁶.

The first iteration of this aspect relates to units wherein each j unit is equal to 0, the index n is equal to 0, and R^(3a) and R^(3b) are taken together to form an oxime unit having the formula ═NOH; compounds of this iteration include compounds having the formula:

wherein R, R¹, and R² are defined herein above. A further iteration includes compounds wherein the ═NOR⁷ unit comprises an R⁷ unit which is C₁-C₄ alkyl, non-limiting examples of which includes [7-(2,6-difluorophenyl)-2-(dimethylamin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone O-methyl-oxime, [7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]]pyrimidin-6-yl]-(4-fluorophenyl)-methanone O-methyl-oxime, and (2-chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone O-methyl-oxime.

Another aspect of L¹ units which can be present with any L unit, includes L¹ units which are units wherein each j unit is equal to 0, the index n is equal to 0, R^(3a) is hydrogen and R^(3b) is —OR⁶. The first iteration of this aspect relates to compounds comprising a L units which are —NH— or —O—, and L¹ units wherein R⁶ is hydrogen, for example, compounds having the formula:

wherein R, R¹, and R² are defined herein above. A further iteration of this aspect relates to R⁶ units which are acyl, thereby providing L¹ having the formula, for example, —CHOC(O)CH₃, and providing compounds having, for example, the formula:

non-limiting examples of which include (2-chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methylester and 3{7-(2-fluoro-phenyl)-6-[(4-fluorophenyl)-hydroxy-methyl]-7H-pyrrolo[pyrimidin-2-ylamino}-2-methyl-butan-2-ol.

Another aspect of L¹ units which can be used in combination with any L unit described herein above, relates to L¹ units wherein each index j unit is equal to 0, the index n is equal to 0, and R^(3a) and R^(3b) are taken together to form a ring comprising from 3 to 7 atoms, for example, compounds comprising a cyclic ketal having the formula:

wherein R, R¹, and R² are defined herein above. A non-limiting example of a compound which comprises this aspect of L and L¹ includes 3-{7-(2,6-difluorophenyl)-6-[2-(4-fluorophenyl)-[1,3]dioxolan-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino}-2-methyl-butan-2-ol.

Yet another aspect of L¹ which can be taken together with any of the L units described herein above, includes R^(3a) and R^(3b) units which are taken together to form a unit having the formula ═CH[C(R⁶)₂]_(x)CO₂R⁶, for example, compounds having the formula:

wherein R⁶ is C₁-C₄ linear alkyl, R, R¹ and R² are the same as defined herein above.

A further aspect of L¹ units relates to compounds comprising a —SO₂— L¹ unit, for example, compounds having the formula:

Other examples of L¹ units include units having the formula —NHC(O)—, —C(O)CH₂—, —C(O)NHC(O)—, —C(O)NH—, and —CH₂C(O)—.

The analogs (compounds) of the present invention are arranged into several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein.

The compounds which comprise Category I of the present invention have the formula:

the first aspect of which relates to 2-heterocycloamino-6-[substituted or unsubstituted]acyl-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines having the formula:

wherein R, R¹, and R² are defined herein below in Table I.

TABLE I No. R R¹ R² 1 piperidin-1-yl 2-fluorophenyl 4-fluorophenyl 2 piperidin-1-yl 2-fluorophenyl 2,6-difluorophenyl 3 piperidin-1-yl 4-fluorophenyl 4-fluorophenyl 4 piperidin-1-yl 4-fluorophenyl 2,6-difluorophenyl 5 piperidin-1-yl 2-chlorophenyl 4-fluorophenyl 6 piperidin-1-yl 2-chlorophenyl 2,6-difluorophenyl 7 piperidin-1-yl 2,6-dichlorophenyl 4-fluorophenyl 8 piperidin-1-yl 2,6-dichlorophenyl 2,6-difluorophenyl 9 piperidin-1-yl 2,6-dimethylphenyl 4-fluorophenyl 10 piperidin-1-yl 2,6-dimethylphenyl 2,6-difluorophenyl 11 piperazin-1-yl 2-fluorophenyl 4-fluorophenyl 12 piperazin-1-yl 2-fluorophenyl 2,6-difluorophenyl 13 piperazin-1-yl 4-fluorophenyl 4-fluorophenyl 14 piperazin-1-yl 4-fluorophenyl 2,6-difluorophenyl 15 piperazin-1-yl 2-chlorophenyl 4-fluorophenyl 16 piperazin-1-yl 2-chlorophenyl 2,6-difluorophenyl 17 piperazin-1-yl 2,6-dichlorophenyl 4-fluorophenyl 18 piperazin-1-yl 2,6-dichlorophenyl 2,6-difluorophenyl 19 piperazin-1-yl 2,6-dimethylphenyl 4-fluorophenyl 20 piperazin-1-yl 2,6-dimethylphenyl 2,6-difluorophenyl 21 morpholin-4-yl 2-fluorophenyl 4-fluorophenyl 22 morpholin-4-yl 2-fluorophenyl 2,6-difluorophenyl 23 morpholin-4-yl 4-fluorophenyl 4-fluorophenyl 24 morpholin-4-yl 4-fluorophenyl 2,6-difluorophenyl 25 morpholin-4-yl 2-chlorophenyl 4-fluorophenyl 26 morpholin-4-yl 2-chlorophenyl 2,6-difluorophenyl 27 morpholin-4-yl 2,6-dichlorophenyl 4-fluorophenyl 28 morpholin-4-yl 2,6-dichlorophenyl 2,6-difluorophenyl 29 morpholin-4-yl 2,6-dimethylphenyl 4-fluorophenyl 30 morpholin-4-yl 2,6-dimethylphenyl 2,6-difluorophenyl 31 pyran-4-yl 2-fluorophenyl 4-fluorophenyl 32 pyran-4-yl 2-fluorophenyl 2,6-difluorophenyl 33 pyran-4-yl 4-fluorophenyl 4-fluorophenyl 34 pyran-4-yl 4-fluorophenyl 2,6-difluorophenyl 35 pyran-4-yl 2-chlorophenyl 4-fluorophenyl 36 pyran-4-yl 2-chlorophenyl 2,6-difluorophenyl 37 pyran-4-yl 2,6-dichlorophenyl 4-fluorophenyl 38 pyran-4-yl 2,6-dichlorophenyl 2,6-difluorophenyl 39 pyran-4-yl 2,6-dimethylphenyl 4-fluorophenyl 40 pyran-4-yl 2,6-dimethylphenyl 2,6-difluorophenyl

The compounds which comprise the first aspect of Category I of the present invention can be prepared by the procedure outlined herein below in Scheme I.

EXAMPLE 1 [7-(2,6-Difluorophenyl)-2-(tetrahydro-pyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone (5)

Preparation of 4-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1): To a solution of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10.0 g, 43.1 mmol) in acetonitrile (107 mL) is added 2,6-difluoroaniline (9.3 mL, 86.2 mmol). The mixture is heated to 90° C. for 4 hours. The reaction is cooled to room temperature and stored at 0° C. for 15 hours. The white precipitate which forms is filtered and washed with 20% EtOAc/hexanes to afford 14.3 g of the desired product which is used without further purification: ¹H NMR (300 MHz, CDCl₃/MeOH) δ 9.70 (s, 1H), 8.20 (s, 1H), 7.82 (s, 2H), 5.23 (s, 2H), 3.18 (s, 3H), 2.25 (s, 3H); ESI⁺ MS: m/z (rel intensity) 326.0 (100, M⁺+H).

Preparation of 4-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (2): To a cold (0° C.) solution of lithium aluminum hydride (145.0 mL of 1M solution in THF, 145.0 mmol) in THF (1.0 L) is added portion-wise 4-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester, 1, (43.0 g, 132.0 mmol). The reaction is allowed to warm to room temp and stirred for an additional 17 hours. The reaction is then re-cooled to 0° C., and H₂O (17 mL) added dropwise to the mixture. After stirring 30 minutes at room temperature, NaOH solution (17 mL of 2N solution) is added followed by H₂O (23 mL). The resulting suspension is filtered through celite and washed thoroughly with EtOAc. The filtrate is concentrated in vacuo to afford 28.4 g of the intermediate alcohol, which is used without further purification: ¹H NMR (300 MHz, CH₃OD) δ 8.02 (s, 1H), 7.26-7.24 (m, 1H), 7.08 (t, J=8.1 Hz, 2H), 4.90 (s, 2H), 2.20 (s, 3H); ESI⁺ MS: m/z (rel intensity) 284.1 (100, M⁺+H).

To a solution of the intermediate alcohol (14.4 g, 50.9 mmol) in CH₂Cl₂ (120 mL) is charged manganese (IV) oxide (44.4 g, 509.0 mmol). After stirring the suspension at room temperature for 17 hours, the mixture is filtered through celite, and washed with CH₂Cl₂. The filtrate is concentrated in vacuo to afford 14.0 g of the desired product as yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.95 (s, 1H), 8.58 (s, 1H), 7.40-6.98 (m, 3H), 2.40 (s, 3H); ESI⁺ MS: m/z (rel intensity) 281.9 (100, M⁺+H).

Preparation of [7-(2,6-difluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone (3): To a solution of 4-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde, 2, (5.4 g, 8.3 mmol) in DMF (107 mL) is added 2-bromo-1-(2-fluorophenyl)-ethanone (2.7 g, 12.5 mmol) and potassium carbonate (8.0 g, 57.7 mmol). The reaction mixture is stirred at room temp for 18 hours then diluted with EtOAc and washed with aqueous saturated NH₄Cl three times. The organic phase is washed with aqueous saturated NaHCO₃ and brine, dried (MgSO₄), filtered and concentrated in vacuo. The resulting residue is purified over silica (10% EtOAc//hexanes) to afford 4.6 g of the desired product as a purple solid: ¹H NMR (300 MHz, CDCl₃) δ 8.98 (s, 1H), 8.00 (dd, J=5.4, 3.4 Hz, 2H), 7.50-7.40 (m, 1H), 7.25-7.05 (m, 5H), 2.52 (s, 3H); ESI⁺ MS: m/z (rel intensity) 400.1 (100, M⁺+H).

Preparation of [7-(2,6-difluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone (4): To a solution of [7-(2,6-difluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone, 3, (4.6 g, 11.5 mmol) in THF:methanol (108 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (28.4 g, 46.1 mmol) in H₂O (83 mL). After stirring the reaction for 1 hour at room temperature, the solution is poured into aqueous saturated NaHCO₃. The aqueous phase is extracted three times with EtOAc and the combined organic phases are dried (MgSO₄), filtered and concentrated in vacuo to afford 4.5 g of the desired product which is used without further purification.

Preparation of [7-(2,6-difluorophenyl)-2-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone (5): To a solution of [7-(2,6-difluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone, 4, (0.50 g, 1.28 mmol) in 1-methyl-2-pyrrolidinone (4 mL) is added 4-aminotetrahydropyran (0.18 g, 1.80 mmol). The reaction mixture is heated to 90° C. for 19 hours after which the reaction is cooled to room temperature and concentrated in vacuo. The crude residue is purified over silica (40% EtOAc/hexanes) to afford 444 mg of the desired product as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.74 (s, 1H), 7.93 (dd, J=9.0, 5.4 Hz, 2H), 7.48-7.39 (m, 1H), 7.20 (t, J=9.0 Hz, 2H), 7.12-7.06 (m, 3H), 4.10-3.95 (m, 3H), 3.49 (t, J=7.6 Hz, 2H), 2.40 (t, J=7.6 Hz, 2H), 2.06-2.01 (m, 2H); HRMS calcd for C₂₄H₁₉F₃N₄O₂ (M+H)⁺ 453.1539; found 453.1551.

(2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(piperidin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.83 (s, 1H), 7.53-7.33 (m, 5H), 7.10 (t, J=7.7 Hz, 2H), 6.89 (s, 1H), 2.86-2.76 (m, 4H), 1.76 (dddd, J=5.4, 5.4, 5.4, 5.4 Hz, 4H), 1.48-1.38 (m, 2H). HRMS calcd for C₂₄H₂₁ClF₂N₅O (M+H)⁺ 468.1403; found 468.1407.

(2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(4-methyl-piperazin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.86 (s, 1H), 7.53-7.35 (m, 5H), 6.92 (s, 1H), 7.12 (t, J=7.8 Hz, 2H), 2.95 (bd m, 4H), 2.70 (bd m, 4H), 2.39 (s, 3H). HRMS calcd for C₂₄H₂₂ClF₂N₆O (M+H)⁺ 483.1512; found 483.1509.

(2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(morpholin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.86 (s, 1H), 7.53-7.37 (m, 5H), 7.10 (dd, J=8.4, 7.7 Hz, 2H), 6.92 (s, 1H), 6.14 (bd s, NH), 3.88 (t, J=4.5 Hz, 4H), 2.93 (t, J=4.5 Hz, 4H). HRMS calcd for C₂₃H₁₉ClF₂N₅O₂ (M+H)⁺ 470.1195; found 470.1187.

[7-(2,6-Difluorophenyl)-2-(4-methyl-piperazin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.90 (s, 1H), 7.96-7.91 (m, 2H), 7.50-7.41 (m, 1H), 7.29-7.06 (m, 6H), 6.00 (s, 1H), 3.11-3.02 (m, 4H), 2.85-2.75 (m, 4H), 2.43 (s, 3H); ESI⁺ MS: m/z (rel intensity) 467.0 (100, M⁺+H).

(4-Fluorophenyl)-[7-(4-fluorophenyl)-2-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 7.96 (dd, J=8.7, 5.4 Hz, 2H), 7.38 (dd, J=9.0, 5.1 Hz, 2H), 7.23-7.15 (m, 4H), 7.03 (s, 1H), 4.05-3.94 (m, 3H), 3.52 (t, J=10.5 Hz, 2H), 2.06-1.97 (m, 2H), 1.64-1.50 (m, 2H). HRMS calcd for C₂₄H₂₁F₂N₄O₂ (M+H)⁺ 435.1633; found 435.1626.

(2-Chlorophenyl)-[7-(4-fluorophenyl)-2-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.68 (s, 1H), 7.55-7.36 (m, 6H), 7.20 (ddd, J=9.0, 9.0, 1.5 Hz, 2H), 6.85 (s, 1H), 4.01-3.97 (m, 3H), 3.51 (t, J=11.4 Hz, 2H), 2.06-1.97 (m, 2H), 1.56 (ddd, J=23.7, 11.4, 4.2 Hz, 2H). HRMS calcd for C₂₄H₂₁ClFN₄O₂ (M+H)⁺ 451.1337; found 451.1328.

(2,4-Dimethylphenyl)-[7-(4-fluorophenyl)-2-(tetrahydropyran-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 7.50 (d, J=7.7 Hz, 2H), 7.39 (dd, J=9.0, 4.8 Hz, 2H), 7.17 (t, J=8.4 Hz, 2H), 7.14-7.06 (m, 2H), 6.82 (s, 1H), 5.32 (bd s, NH), 4.06-3.94 (m, 3H), 3.52 (ddd, J=15.6, 15.6, 1.8 Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.08-2.00 (m, 2H), 1.64-1.51 (m, 2H). HRMS calcd for C₂₆H₂₆FN₄O₂ (M+H)⁺ 445.2040; found 445.2031.

The second aspect of Category I relates to 2-aryloxy-6-[substituted or unsubstituted]acyl-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines having the formula:

wherein L, R, R¹, and R² are defined herein below in Table II.

TABLE II No. L R R¹ R² 41 —O— phenyl 2-fluorophenyl 4-fluorophenyl 42 —O— phenyl 2-fluorophenyl 2,6- difluorophenyl 43 —O— phenyl 4-fluorophenyl 4-fluorophenyl 44 —O— phenyl 4-fluorophenyl 2,6- difluorophenyl 45 —O— phenyl 2-chlorophenyl 4-fluorophenyl 46 —O— phenyl 2-chlorophenyl 2,6- difluorophenyl 47 —O— phenyl 2,6- 4-fluorophenyl dichlorophenyl 48 —O— phenyl 2,6- 2,6- dichlorophenyl difluorophenyl 49 —O— phenyl 2,6- 4-fluorophenyl dimethylphenyl 50 —O— phenyl 2,6- 2,6- dimethylphenyl difluorophenyl 51 —NH— phenyl 2-fluorophenyl 4-fluorophenyl 52 —NH— phenyl 2-fluorophenyl 2,6- difluorophenyl 53 —NH— phenyl 4-fluorophenyl 4-fluorophenyl 54 —NH— phenyl 4-fluorophenyl 2,6- difluorophenyl 55 —NH— phenyl 2-chlorophenyl 4-fluorophenyl 56 —NH— phenyl 2-chlorophenyl 2,6- difluorophenyl 57 —NH— phenyl 2,6- 4-fluorophenyl dichlorophenyl 58 —NH— phenyl 2,6- 2,6- dichlorophenyl difluorophenyl 59 —NH— phenyl 2,6- 4-fluorophenyl dimethylphenyl 60 —NH— phenyl 2,6- 2,6- dimethylphenyl difluorophenyl 61 —O— 2,6-difluorophenyl 2-fluorophenyl 4-fluorophenyl 62 —O— 2,6-difluorophenyl 2-fluorophenyl 2,6- difluorophenyl 63 —O— 2,6-difluorophenyl 4-fluorophenyl 4-fluorophenyl 64 —O— 2,6-difluorophenyl 4-fluorophenyl 2,6- difluorophenyl 65 —O— 2,6-difluorophenyl 2-chlorophenyl 4-fluorophenyl 66 —O— 2,6-difluorophenyl 2-chlorophenyl 2,6- difluorophenyl 67 —O— 2,6-difluorophenyl 2,6- 4-fluorophenyl dichlorophenyl 68 —O— 2,6-difluorophenyl 2,6- 2,6- dichlorophenyl difluorophenyl 69 —O— 2,6-difluorophenyl 2,6- 4-fluorophenyl dimethylphenyl 70 —O— 2,6-difluorophenyl 2,6- 2,6- dimethylphenyl difluorophenyl 71 —NH— 2,6-difluorophenyl 2-fluorophenyl 4-fluorophenyl 72 —NH— 2,6-difluorophenyl 2-fluorophenyl 2,6- difluorophenyl 73 —NH— 2,6-difluorophenyl 4-fluorophenyl 4-fluorophenyl 74 —NH— 2,6-difluorophenyl 4-fluorophenyl 2,6- difluorophenyl 75 —NH— 2,6-difluorophenyl 2-chlorophenyl 4-fluorophenyl 76 —NH— 2,6-difluorophenyl 2-chlorophenyl 2,6- difluorophenyl 77 —NH— 2,6-difluorophenyl 2,6- 4-fluorophenyl dichlorophenyl 78 —NH— 2,6-difluorophenyl 2,6- 2,6- dichlorophenyl difluorophenyl 79 —NH— 2,6-difluorophenyl 2,6- 4-fluorophenyl dimethylphenyl 80 —NH— 2,6-difluorophenyl 2,6- 2,6- dimethylphenyl difluorophenyl

The following are non-limiting examples of the second aspect of Category II according to the present invention.

(2-Chlorophenyl)-[2-(2,6-difluorophenoxy)-7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.91 (s, 1H), 7.55-7.36 (m, 6H), 7.24-6.98 (m, 6H). HRMS calcd for C₂₅H₁₃ClF₄N₃O₂ (M+H)⁺ 498.0632; found 498.0616.

(2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.92 (s, 1H), 7.55-7.40 (m, 5H), 7.27-7.23 (m, 4H), 7.11 (t, J=8.4 Hz, 2H), 7.05 (s, 1H). HRMS calcd for C₂₅H₁₅ClF₂N₃O₂ (M+H)⁺ 462.0821; found 462.0830.

[7-(2,6-Difluorophenyl)-2-(2,6-difluorophenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 7.87 (dd, J=8.7, 5.4 Hz, 2H), 7.41-7.32 (m, 1H), 7.19-7.09 (m, 4H), 7.00 (t, J=8.1 Hz, 2H), 6.89 (t, J=8.1 Hz, 2H). HRMS calcd for C₂₅H₁₄F₅N₄O (M+H)⁺ 481.1088; found 481.1100.

[7-(2,6-Difluorophenyl)-2-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.98 (s, 1H), 7.98 (dd, J=6.6, 5.5 Hz, 2H), 7.47-7.30 (m, 3H), 7.29-7.20 (m, 6H), 7.09 (t, J=8.1 Hz, 2H), HRMS calcd for C₂₅H₁₄F₃N₃O₂ (M+H)⁺ 446.1116; found 446.1114.

[2-(2,6-Difluorophenylamino)-7-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.84 (s, 1H), 7.98 (dd, J=5.5, 3.1 Hz, 2H), 7.65 (t, J=7.5, 1H), 7.41-6.90 (m, 8H), 4.15 (dd, J=14.1, 7.1 Hz, 1H); HRMS calcd for C₂₅H₁₄F₄N₄O (M+H)⁺ 463.1182; found 463.1204.

(4-Fluorophenyl)-[7-(4-fluorophenyl)-2-(1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.69 (s, 1H), 7.93 (dd, J=5.5, 3.3 Hz, 2H), 7.35-7.10 (m, 11H), 6.98 (s, 1H), 5.82 (br s, 1H), 4.90 (br s, 1H), 1.55 (d, J=6.8 Hz, 3H); HRMS calcd for C₂₇H₂₀F₂N₄O (M+H)⁺ 455.1683, found 455.1670.

(2-Chlorophenyl)-[7-(4-fluorophenyl)-2-(1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H), 7.47-7.10 (m, 13H), 6.81 (s, 1H), 5.95 (br s, 1H), 5.00 (br s, 1H), 1.55 (d, J=6.8 Hz, 3H); HRMS calcd for C₂₇H₂O ClFN₄O (M+H)⁺ 471.1388, found 471.1382.

The third aspect of Category I relates to 2-[substituted or unsubstituted]alkylamino-6-[substituted or unsubstituted]acyl-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines having the formula:

wherein R, R¹, and R² are defined herein below in Table III.

TABLE III No. R R¹ R² 81 2-methyl-2-hydroxy-1-(S)- 4-fluorophenyl 4-fluorophenyl methylpropyl 82 2-methoxy-1-(S)-methylethyl 4-fluorophenyl 4-fluorophenyl 83 2-methyl-2-cyano-1-(S)- 4-fluorophenyl 4-fluorophenyl methylpropyl 84 2-methyl-2-hydroxy-1-(R)- 4-fluorophenyl 4-fluorophenyl methylpropyl 85 2-methoxy-1-(R)- 4-fluorophenyl 4-fluorophenyl methylethyl 86 2-methyl-2-cyano-1-(R)- 4-fluorophenyl 4-fluorophenyl methylpropyl 87 1-(S)-methylpropyl 4-fluorophenyl 4-fluorophenyl 88 1-(R)-methylpropyl 4-fluorophenyl 4-fluorophenyl 89 N,N-dimethylamino 4-fluorophenyl 4-fluorophenyl 90 N,N-diethylamino 4-fluorophenyl 4-fluorophenyl 91 2-methyl-2-hydroxy-1-(S)- 4-fluorophenyl 2,6- methylpropyl difluorophenyl 92 2-methoxy-1-(S)-methylethyl 4-fluorophenyl 2,6- difluorophenyl 93 2-methyl-2-cyano-1-(S)- 4-fluorophenyl 2,6- methylpropyl difluorophenyl 94 2-methyl-2-hydroxy-1-(R)- 4-fluorophenyl 2,6- methylpropyl difluorophenyl 95 2-methoxy-1-(R)-methylethyl 4-fluorophenyl 2,6- difluorophenyl 96 2-methyl-2-cyano-1-(R)- 4-fluorophenyl 2,6- methylpropyl difluorophenyl 97 1-(S)-methylpropyl 4-fluorophenyl 2,6- difluorophenyl 98 1-(R)-methylpropyl 4-fluorophenyl 2,6- difluorophenyl 99 N,N-dimethylamino 4-fluorophenyl 2,6- difluorophenyl 100 N,N-diethylamino 4-fluorophenyl 2,6- difluorophenyl 101 2-methyl-2-hydroxy-1-(S)- 2-chlorophenyl 4-fluorophenyl methylpropyl 102 2-methoxy-1-(S)-methylethyl 2-chlorophenyl 4-fluorophenyl 103 2-methyl-2-cyano-1-(S)- 2-chlorophenyl 4-fluorophenyl methylpropyl 104 2-methyl-2-hydroxy-1-(R)- 2-chlorophenyl 4-fluorophenyl methylpropyl 105 2-methoxy-1-(R)-methylethyl 2-chlorophenyl 4-fluorophenyl 106 2-methyl-2-cyano-1-(R)- 2-chlorophenyl 4-fluorophenyl methylpropyl 107 1-(S)-methylpropyl 2-chlorophenyl 4-fluorophenyl 108 1-(R)-methylpropyl 2-chlorophenyl 4-fluorophenyl 109 N,N-dimethylamino 2-chlorophenyl 4-fluorophenyl 110 N,N-diethylamino 2-chlorophenyl 4-fluorophenyl 111 2-methyl-2-hydroxy-1-(S)- 2-chlorophenyl 4-fluorophenyl methylpropyl 112 2-methoxy-1-(S)-methylethyl 2-chlorophenyl 2,6- difluorophenyl 113 2-methyl-2-cyano-1-(S)- 2-chlorophenyl 2,6- methylpropyl difluorophenyl 114 2-methyl-2-hydroxy-1-(R)- 2-chlorophenyl 2,6- methylpropyl difluorophenyl 115 2-methoxy-1-(R)-methylethyl 2-chlorophenyl 2,6- difluorophenyl 116 2-methyl-2-cyano-1-(R)- 2-chlorophenyl 2,6- methylpropyl difluorophenyl 117 1-(S)-methylpropyl 2-chlorophenyl 2,6- difluorophenyl 118 1-(R)-methylpropyl 2-chlorophenyl 2,6- difluorophenyl 119 N,N-dimethylamino 2-chlorophenyl 2,6- difluorophenyl 120 N,N-diethylamino 2-chlorophenyl 2,6- difluorophenyl

The following are non-limiting examples of the third aspect of Category I.

N,N-Dimethyl-N′-[7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-hydrazino-(4-fluoro-phenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.90 (s, 1H), 7.92 (dd, J=8.8, 5.5 Hz, 2H), 7.50-7.39 (m, 1H), 7.20 (t, J=8.7 Hz, 2H), 7.10 (t, J=8.7 Hz, 2H), 7.09 (s, 1H), 6.01 (bd s, NH), 2.70 (s, 6H); HRMS calcd for C₂₁H₁₆F₃N₅O (M+H)⁺ 412.1385; found 412.1390.

N,N-Dimethyl-N′-(2-chlorophenyl)-[7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-hydrazino-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 7.59-7.32 (m, 5H), 7.17 (t, J=8.4 Hz, 2H), 6.95 (s, 1H), 2.72 (s, 6H). HRMS calcd for C₂₁H₁₇ClF₂N₅O (M+H)⁺ 468.1403; found 468.1407.

(S)-(2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H), 7.58-7.11 (m, 7H), 6.92 (s, 1H), 4.03 (m, 1H), 1.27 (s, 9H). HRMS calcd for C₂₄H₂₁ClF₂N₄O₂ (M+H)⁺ 471.1399; found 471.1405.

(S)-[2-sec-Butylamino-7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(2-chloro-phenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.64 (s, 1H), 7.52-7.34 (m, 5H), 7.11 (t, J=8.1 Hz, 2H), 6.88 (s, 1H), 5.42 (bd s, NH), 3.94 (m, 1H), 1.65-1.46 (m, 2H), 1.18 (d, J=6.4 Hz, 3H), 0.92 (t, J=7.3 Hz, 3H). HRMS calcd for C₂₃H₂₀ClF₂N₄O (M+H)⁺ 441.1294; found 441.1276.

(S)-[7-(2,6-Difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 7.86 (dd, J=8.4, 5.1 Hz, 2H), 7.46-7.36 (m, 1H), 7.15 (t, J=8.4 Hz, 2H), 7.09-7.03 (m, 3H), 4.00 (bd m, 1H), 1.17 (d, J=7.2 Hz, 3H), 1.16 (s, 6H). HRMS calcd for C₂₄H₂₂F₅N₄O₂ (M+H)⁺ 455.1695; found 455.1716.

(2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-methoxyamino-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.88 (s, 1H), 7.94 (s, 1H), 7.54-7.36 (m, 4H), 7.30 (s, 1H), 7.12 (t, J=8.2 Hz, 2H) 6.98 (s, 1H), 3.88 (s, 3H): HRMS calcd for C₂₀H₁₃ClF₂N₄O₂ (M+H)⁺ 415.0773; found 415.0755.

(S)-(4-Fluoro-phenyl)-[7-(2-fluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 7.96-7.92 (m, 2H), 7.60-7.52 (m, 1H), 7.47-7.41 (m, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.25-7.16 (m, 3H), 7.00 (s, 1H), 5.50 (bd s, NH), 4.10-3.95 (m, 1H), 1.25-1.21 (m, 9H). HRMS calcd for C₂₄H₂₃F₂N₄O₂ (M+H)⁺ 437.1789; found 437.1795.

[2-Cyclopropylamino-7-(2-fluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.80 (s, 1H), 7.99-7.94 (m, 2H), 7.63-7.60 (m, 1H), 7.44-7.6.99 (m, 6H), 5.65 (br s, 1H), 2.87 (s, 1H), 0.80 (s, 2H), 0.57 (s, 2H); HRMS calcd for C₂₂H₁₆F₂N₄O (M+H)⁺ 391.1370; found 391.1387.

(2-Chloro-phenyl)-[7-(4-fluoro-phenyl)-2-(2-methoxy-1-methyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 7.50-7.34 (m, 6H), 7.19 (t, J=8.3 Hz, 2H), 6.84 (s, 1H), 5.70 (brS, 1H), 4.22 (br s, 1H), 3.39 (s, 3H), 2.37 (t, J=6.8 Hz, 3H); HRMS calcd for C₂₃H₂₀ClFN₄O₂ (M+H)⁺ 439.1337; found 439.1326.

(S)-(4-Fluoro-phenyl)-7-(4-fluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 7.36 (dd, J=9.0, 5.1 Hz, 2H), 7.25-7.16 (m, 6H), 7.02 (s, 1H), 5.55 (bd s, NH), 4.05 (m, 1H), 2.75 (s, 9H). HRMS calcd for C₂₄H₂₃F₂N₄O₂ (M+H)⁺ 437.1789; found 437.1797.

(S)-(2-Chloro-phenyl)-[7-(4-fluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 1H), 7.51-7.37 (m, 5H), 7.24-7.16 (m, 3H), 6.85 (s, 1H), 4.05 (m, 1H), 1.25 (d, J=8.2 Hz, 3H), 1.21 (s, 6H). HRMS calcd for C₂₄H₂₂ClFN₄O₂ (M+H)⁺ 453.1494; found 453.1500.

(S)-[2-sec-Butylamino-7-(4-fluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(2-chloro-phenyl)-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H), 7.49-7.36 (m, 6H), 7.20 (t, J=7.8 Hz, 2H), 6.83 (s, 1H), 5.35 (bd s, NH), 3.98 (m, 1H), 1.56 (dddd, J=13.6, 8.8, 8.8, 8.8 Hz, 2H), 1.19 (d, J=8.8 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H). HRMS calcd for C₂₄H₂₁ClFN₄O₂ (M+H)⁺ 423.1388; found 423.1371.

(2,4-Dimethyl-phenyl)-[7-(4-fluoro-phenyl)-2-(2-hydroxy-1,2-dimethylpropylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.65 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.42-7.36 (m, 2H), 7.19 (t, d=8.4 Hz, 2H), 7.12-7.06 (m, 2H), 6.82 (s, 1H), 5.49 (br s, 1H), 4.03 (br s, 1H), 2.39 (d, J=7.7 Hz, 6H), 1.25-1.20 (m, 9H); HRMS calcd for C₂₆H₂₈FN₄O₂ (M+H)⁺ 447.2216; found 447.2196.

(S)-(2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-methoxy-1-methyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.67 (s, 1H), 7.52-7.35 (m, 5H), 7.14-7.07 (m, 2H), 6.89 (s, 1H), 5.70 (bd s, NH), 4.20 (bd s, 1H), 3.47-3.39 (m, 1H), 3.34 (s, 3H), 1.25 (d, J=6.6 Hz, 3H). HRMS calcd for C₂₃H₂₀ClF₂N₄O₂ (M+H)⁺ 457.1243; found 457.1247.

(2-Chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-urylamino-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 7.7.49-7.30 (m, 9H), 6.95 (s, 2H), 2.88 (s, 1H); HRMS calcd for C₂₀H₁₃F₂N₆O₂ (M+H)⁺ 443.0834, found 443.0824.

The compounds which comprise Category II of the present invention have the formula:

the first aspect of which relates to 2-[substituted or unsubstituted]alkylamino-6-[substituted or unsubstituted]aryl-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines methanone oximes having the formula:

wherein R, R¹, and R² are defined herein below in Table IV.

TABLE IV No. R R¹ R² 121 2-methyl-2-hydroxy-1- 4-fluorophenyl 4-fluorophenyl (S)-methylpropyl 122 2-methyl-2-hydroxy-1- 4-fluorophenyl 2,6-difluorophenyl (S)-methylpropyl 123 2-methoxy-1-(S)- 4-fluorophenyl 4-fluorophenyl methylethyl 124 2-methoxy-1-(S)- 4-fluorophenyl 2,6-difluorophenyl methylethyl 125 2-methyl-2-cyano-1- 4-fluorophenyl 4-fluorophenyl (S)-methylpropyl 126 2-methyl-2-cyano-1- 4-fluorophenyl 2,6-difluorophenyl (S)-methylpropyl 127 1-(S)-methylpropyl 4-fluorophenyl 4-fluorophenyl 128 1-(S)-methylpropyl 4-fluorophenyl 2,6-difluorophenyl 129 N,N-dimethylamino 4-fluorophenyl 4-fluorophenyl 130 N,N-dimethylamino 4-fluorophenyl 2,6-difluorophenyl 131 2-methyl-2-hydroxy-1- 2-chlorophenyl 4-fluorophenyl (S)-methylpropyl 132 2-methyl-2-hydroxy-1- 2-chlorophenyl 2,6-difluorophenyl (S)-methylpropyl 133 2-methoxy-1-(S)- 2-chlorophenyl 4-fluorophenyl methylethyl 134 2-methoxy-1-(S)- 2-chlorophenyl 2,6-difluorophenyl methylethyl 135 2-methyl-2-cyano-1- 2-chlorophenyl 4-fluorophenyl (S)-methylpropyl 136 2-methyl-2-cyano-1- 2-chlorophenyl 2,6-difluorophenyl (S)-methylpropyl 137 1-(S)-methylpropyl 2-chlorophenyl 4-fluorophenyl 138 1-(S)-methylpropyl 2-chlorophenyl 2,6-difluorophenyl 139 N,N-dimethylamino 2-chlorophenyl 4-fluorophenyl 140 N,N-dimethylamino 2-chlorophenyl 2,6-difluorophenyl 141 2-methyl-2-hydroxy-1- 4-fluorophenyl 4-fluorophenyl (S)-methylpropyl 142 2-methyl-2-hydroxy-1- 4-fluorophenyl 2,6-difluorophenyl (S)-methylpropyl 143 2-methoxy-1-(S)- 4-fluorophenyl 4-fluorophenyl methylethyl 144 2-methoxy-1-(S)- 4-fluorophenyl 2,6-difluorophenyl methylethyl 145 2-methyl-2-cyano-1- 4-fluorophenyl 4-fluorophenyl (S)-methylpropyl 146 2-methyl-2-cyano-1- 4-fluorophenyl 2,6-difluorophenyl (S)-methylpropyl 147 1-(S)-methylpropyl 4-fluorophenyl 4-fluorophenyl 148 1-(S)-methylpropyl 4-fluorophenyl 2,6-difluorophenyl 149 N,N-dimethylamino 4-fluorophenyl 4-fluorophenyl 150 N,N-dimethylamino 4-fluorophenyl 2,6-difluorophenyl 151 2-methyl-2-hydroxy-1- 2,6-difluorophenyl 4-fluorophenyl (S)-methylpropyl 152 2-methyl-2-hydroxy-1- 2,6-di fluorophenyl 2,6-difluorophenyl (S)-methylpropyl 153 2-methoxy-1-(S)- 2,6-difluorophenyl 4-fluorophenyl methylethyl 154 2-methoxy-1-(S)- 2,6-difluorophenyl 2,6-difluorophenyl methylethyl 155 2-methyl-2-cyano-1- 2,6-difluorophenyl 4-fluorophenyl (S)-methylpropyl 156 2-methyl-2-cyano-1- 2,6-difluorophenyl 2,6-difluorophenyl (S)-methylpropyl 157 1-(S)-methylpropyl 2,6-difluorophenyl 4-fluorophenyl 158 1-(S)-methylpropyl 2,6-difluorophenyl 2,6-difluorophenyl 159 N,N-dimethylamino 2,6-difluorophenyl 4-fluorophenyl 160 N,N-dimethylamino 2,6-difluorophenyl 2,6-difluorophenyl

The compounds which comprise the first aspect of Category II can be prepared beginning with intermediates prepared according to Scheme I, for example, compound 6 depicted in Scheme II herein below.

EXAMPLE 2 [7-(2,6-Difluorophenyl)-2-(dimethylamin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone-oxime (7)

Intermediate compound N,N-dimethyl-N′-[7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-hydrazino-(4-fluoro-phenyl)-methanone, 6, used for the preparation of the following analog, can be prepared according to the procedure outlined herein above in Scheme I.

Preparation of [7-(2,6-difluoro-phenyl)-2-(dimethylamin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone-oxime (7): To a solution of N,N-dimethyl-A-[7-(2,6-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-2-hydrazino-(4-fluoro-phenyl)-methanone, 6, (0.50 g, 1.22 mmol) in pyridine (2 mL) is added hydroxylamine hydrochloride (0.85 g, 12.20 mmol) and the mixture heated to 60 ° C. overnight. The reaction is then cooled to room temperature and concentrated in vacuo. The crude product is dissolved in EtOAc and washed with H₂O, brine, dried (MgSO₄), filtered and re-concentrated in vacuo to give a yellow solid which is re-crystallized from EtOAc/hexanes to afford 506 mg of the desired product as a yellow powder: ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 7.44-7.36 (m, 2H), 7.22-7.17 (m, 3H), 7.08 (t, J=8.8 Hz, 2H), 6.95 (dd, J=8.4, 8.0 Hz, 1H), 6.32 (d, J=13.2 Hz, 1H), 6.00 (s, 1H), 3.81 (m, 1H), 1.12-1.08 (m, 9H); HRMS calcd for C₂₁H₁₈F₃N₆O (M+H)⁺ 427.1494, found 427.1496.

[7-(2,6-Difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone oxime: ¹H NMR (300 MHz, CDCl₃) δ 8.52 (d, J=7.5 Hz, 1H), 7.49-6.80 (m, 8H), 6.46 (s, 1H), 5.74 (br s, 1H), 3.95 (br s, 1H), 1.30-1.18 (m, 9H); HRMS calcd for C₂₄H₂₂F₃N₅O₂ (M+H)⁺ 470.1804, found 470.1823.

(2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone oxime: ¹H NMR (300 MHz, CDCl₃) δ 8.70 (br s, 1H), 8.42 (s, 1H), 7.55-7.25 (m, 5H), 7.02 (t, J=7.1 Hz, 2H), 6.25 (s, 1H), 5.26 (d, J=7.1 Hz, 1H), 4.14 (dd, J=9.1, 7.1 Hz, 3H), 3.93 (t=7.1 Hz, 1H), 1.21-1.15 (m, 9H); HRMS calcd for C₂₄H₂₄F₂N₅O₂ (M+H)⁺ 452.1898, found 452.1902.

(2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone oxime: ¹H NMR (300 MHz, CDCl₃) δ 8.70 (br s, 1H), 8.42 (s, 1H), 7.55-7.25 (m, 5H), 7.02 (t, J=7.1 Hz, 2H), 6.25 (s, 1H), 5.26 (d, J=7.1 Hz, 1H), 4.14 (dd, J=9.1, 7.1 Hz, 3H), 3.93 (t=7.1 Hz, 1H), 1.21-1.15 (m, 9H); HRMS calcd for C₂₄H₂₂ClF₂N₅O₂ (M+H)⁺ 486.1508, found 486.1514.

Another iteration of this aspect relates to O-methyl oximes having the formula:

which can be prepared by the following procedure.

Preparation of [7-(2,6-Difluorophenyl)-2-(dimethylamin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone O-methyl-oxime: To a solution of [7-(2,6-difluoro-phenyl)-2-(dimethyl-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone (0.478 g, 1.04 mmol) in 1-methyl-2-pyrrolidinone (3 mL) is added 1,1-dimethylhydrazine (0.158 mL, 2.08 mmol) and the mixture was heated at 90° C. overnight. The reaction is cooled to room temperature diluted with ethyl acetate and washed with sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a brown oil which is purified over silica (hexane:ethyl acetate (6:4), then with ethyl acetate) to afford 100 mg (23% yield) of a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 7.44-7.36 (m, 2H), 7.22-7.17 (m, 3H), 7.08 (t, J=8.8 Hz, 2H), 6.95 (dd, J=8.4, 8.0 Hz, 1H), 6.32 (d, J=13.2 Hz, 1H), 6.00 (s, 1H), 3.81 (m, 1H), 1.12-1.08 (m, 9H); HRMS calcd for C₂₂H₂₀F₃N₆O (M+H)⁺ 441.1651, found 441.1650.

The following are further non-limiting examples of this iteration.

[7-(2,6-Difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone O-methyl-oxime: ¹H NMR (300 MHz, CDCl₃) δ 8.53 (d, J=7.5 Hz, 1H), 7.65-6.90 (m 8H), 5.44 (br s, 1H), 4.00 (d, J=6.4 Hz, 1H), 3.54 (s, 3H), 1.30-1.18 (m, 9H); HRMS calcd for C₂₅H₂₄F₃N₅O₂ (M+H)⁺ 484.1960, found 484.1943.

(2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone O-methyl-oxime: ¹H NMR (300 MHz, CDCl₃) δ 8.46 (s, 1H), 7.51-7.32 (m, 5H), 7.12-7.04 (m, 2H), 6.20 (s, 1H), 5.22-5.20 (m, 1H), 3.97 (s, 1H), 3.53 (s, 3H), 1.23-1.18 (m, 9H); HRMS calcd for C₂₅H₂₄ClF₂N₅O₂ (M+H)⁺ 500.1665, found 500.1667.

[7-(2,6-Difluorophenyl)-2-(piperidin-1-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluorophenyl)-methanone O-methyl-oxime: ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 7.44-7.36 (m, 2H), 7.22-7.17 (m, 3H), 7.08 (t, J=8.8 Hz, 2H), 6.95 (dd, J=8.4, 8.0 Hz, 1H), 6.32 (d, J=13.2 Hz, 1H), 6.00 (s, 1H), 3.81 (m, 1H), 1.12-1.08 (m, 9H); HRMS calcd for C₂₅H₂₄F₃N₆O (M+H)⁺ 481.1964, found 481.1957.

A further aspect of Category II according to the present invention wherein L¹ units are —CHOH— units can be prepared from intermediates, such as compound 8, by the procedure described herein below and outlined in Scheme III.

EXAMPLE 3 3-[6-[(2-Chlorophenyl)-hydroxy-methyl}-7-(2,6-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-2-methyl-butan-2-ol (9)

Intermediate compound (S)-(2-chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 8, used for the preparation of the following analog, can be prepared according to the procedure outlined herein above in Scheme I.

Preparation of 3-[6-[(2-chlorophenyl)-hydroxy-methyl}-7-(2,6-difluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-2-methyl-butan-2-ol (9): To a solution of (S)-(2-chloro-phenyl)-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 8, (1.0 g, 2.1 mmol) in ethanol (2.4 mL) is added sodium borohydride (0.3 g, 8.5 mmol) and the mixture stirred overnight at room temperature. Aqueous ammonium chloride solution is then added and the mixture is extracted with EtOAc several times and the organic phases combined washed with water, brine, dried (MgSO₄), filtered and concentrated in vacuo. The resulting residue is purified over silica (50% EtOAc/hexanes, then 100% EtOAc) to afford 470 mg of the desired product as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 7.44-7.36 (m, 2H), 7.22-7.17 (m, 3H), 7.08 (t, J=8.8 Hz, 2H), 6.95 (dd, J=8.4, 8.0 Hz, 1H), 6.32 (d, J=13.2 Hz, 1H), 6.00 (s, 1H), 3.81 (m, 1H), 1.12-1.08 (m, 9H); HRMS calcd for C₂₄H₂₃ClF₂N₄O₂ (M+H)⁺ 473.1556, found 473.1542.

The following are non-limiting examples of this aspect of Category III.

(2-Chlorophenyl)-[7-(2,6-difluorophenyl)-2-(morpholin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanol: ¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H), 7.57-7.40 (m, 2H), 7.33-7.20 (m, 3H), 7.15-6.98 (m, 2H), 6.32 (s, 1H), 6.13 (s, 1H), 5.80 (s, 1H), 3.86 (s, 4H), 2.88 (s, 4H); HRMS calcd for C₂₃H₂₀ClF₂N₅O₂ (M+H)⁺ 472.1352, found 472.1343.

An iteration of this aspect relates to O-acyl, inter alia, O-acetyl analogs, for example, wherein L¹ is —CHOC(O)CH₃, having the formula:

which can be prepared by the procedure described herein below and outlined in Scheme IV.

EXAMPLE 4

Preparation of acetic acid (2-chlorophenyl)-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]methylester (10): To a solution of 3-[6-[(2-chloro-phenyl)-hydroxy-methyl}-7-(2,6-difluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-2-methyl-butan-2-ol, 9, (0.47 g, 1.00 mmol) and triethylamine (0.60 ml, 4.0 mmol), in pyridine (5 ml) is added dropwise acetyl chloride (0.08 ml, 2.20 mmol). The reaction mixture is stirred under argon at room temperature for 48 hours. Ethyl acetate is added to the mixture and the resulting mixture is washed with water, brine, dried (MgSO₄), filtered and concentrated in vacuo. The resulting residue is purified over silica (40% EtOAc/hexanes) to afford 30 mg of the desired: ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 7.52-7.10 (m, 7H), 6.11 (d, J=5.3 Hz, 1H), 4.00-3.91 (m, 1H), 1.97 (d, J=5.9 Hz, 3H), 1.50 (br s, 1H), 1.23 (s, 3H), 1,19 (s, 3H); HRMS calcd for C₂₆H₂₅ClF₂N₄O₃ (M+H)⁺ 515.1662, found 515.1644.

A non-limiting example of this iteration includes:

3 {7-(2-Fluoro-phenyl)-6-[(4-fluorophenyl)-hydroxy-methyl]-7H-pyrrolo[pyrimidin-2-ylamino}-2-methyl-butan-2-ol: ¹H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 7.30-6.92 (m, 8H), 6.40 (dd, J=4.0, 3.7 Hz, 1H), 5.72 (d, J=5.5 Hz, 1H), 5.22 (br s, 1H), 3.92 (dd, J=14.6, 7.3 Hz, 1H), 1.22-1.16 (m, 9H); HRMS calcd for C₂₄H₂₄F₂N₄O₂ (M+H)⁺ 439.1946, found 439.1960.

The third aspect of Category II relates to L¹ units wherein R^(3a) and R^(3b) or R^(4a) and R^(4b) can be taken together to form a ring comprising from 3 to 7 atoms, for example, the cyclic ketals having the formula:

Compounds which comprise this aspect can be prepared beginning with intermediates such as compound 8, as described here below and depicted in Scheme V.

EXAMPLE 5

Preparation of 3-{7-(2,6-difluorophenyl)-6-[2-(4-fluorophenyl)-[1,3]dioxolan-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino}-2-methyl-butan-2-ol (10): To a solution of (S)-(2-chlorophenyl)-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 8, (0.17 g, 0.36 mmol) and ethylene glycol (0.045 ml, 0.726 mmol) in CH₂Cl₂ (2 ml) is added borane trifluoride etherate (0.02 ml, 0.15 mmol) and the mixture is stirred for 17 hours at room temperature. Additional borane trifluoride etherate (0.01 ml) is added as needed to drive the reaction to completion. The reaction mixture is diluted with H₂O and extracted with EtOAc the combined organic phases are washed with additional H₂O, aqueous NH₄Cl solution, dried (MgSO₄), filtered and concentrated in vacuo. The residue is purified over silica (50% EtOAc/hexanes, then 80% EtOAc/hexanes) to afford 68 mg of the desired product as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.48 (s, 1H), 7.43-6.92 (m, 7H), 6.47 (s, 1H), 8.0 Hz, 1H), 3.98-3.84 (m, 6H), 1.22-1.15 (m, 9H); HRMS calcd for C₂₆H₂₅F₃N₄O₃ (M+H)⁺ 499.1957, found 499.1946.

The fourth aspect of Category II relates to L¹ units wherein R^(3a) and R^(3b) or R^(4a) and R^(4b) are be taken together to form a unit having the formula ═CH[C(R⁶)₂]_(x)CO₂R⁶, for example, compounds having the formula:

The compound of this aspect of Category II can be prepared by the procedure described herein below and outlined in Scheme VI.

EXAMPLE 6 3-(2-Chlorophenyl)-3-[7-(2,6-difluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester (15)

Preparation of 3-(2-chlorophenyl)-3-[7-(2,6-difluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester (13): To a suspension of sodium hydride (0.08 g of 60% dispersion in mineral oil, 1.26 mmol) in THF (3 mL) is added triethylphosphonoacetate (0.25 mL, 1.26 mmol) dropwise. After stirring the mixture at room temperature for 5 minutes, a solution of 3-(2-chlorophenyl)-[7-(2,6-difluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 12, (0.50 g, 1.20 mmol) in THF (4 mL) is added dropwise. After stirring the mixture at room temp for 2 hours, the reaction mixture is heated to reflux for 2 days. The mixture is dissolved in CHCl₃ and washed with aqueous saturated NH₄Cl solution, dried (MgSO₄), filtered, and concentrated in vacuo. The crude residue is purified over silica (25%

EtOAc/hexanes) to afford 390 mg of the desired product: ¹H NMR (300 MHz, CDCl₃) δ 8.79 (s, 1H), 7.45-7.10 (m, 5H), 7.08-6.97 (m, 1H), 6.35 (s, 1H), 6.20 (s, 1H), 4.00 (q, J=6.9 Hz, 2H), 2.45 (s, 3H), 1.05 (t, J=6.9 Hz, 3H); ESI⁺ MS: m/z (rel intensity) 485.9 (100, M⁺+H).

Preparation of 3-(2-chlorophenyl)-3-[7-(2,6-difluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester (14): To a solution of 3-(2-chloro-phenyl)-3-[7-(2,6-difluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester, 13, (0.33 g, 0.68 mmol) in THF/methanol (4 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (1.46 g, 2.38 mmol) in H₂O (4 mL). After stirring the reaction for 1 hour at room temperature, the solution is poured into aqueous saturated NaHCO₃. The aqueous phase is extracted with CHCl₃ and the combined organic phases are dried (MgSO₄), filtered and concentrated in vacuo to afford 0.31 g of the desired product which is used without further purification.

Preparation of 3-(2-chlorophenyl)-3-[7-(2,6-difluoro-phenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester (15): To a solution of 3-(2-chloro-phenyl)-3-[7-(2,6-difluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-acrylic acid ethyl ester, 14, (0.30 g, 0.59 mmol)) in N-methylpyrrolidinone (4 mL) is added diisopropylethylamine (0.41 mL, 2.36 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.10 g, 0.71 mmol). After heating the reaction at 90° C. for 21 hours, an additional equivalent of 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.08 g, 0.59 mmol) is added and the mixture heated at 120° C. for 4 hours. The reaction is cooled to room temp and then diluted with aqueous saturated NH₄Cl solution. The aqueous phase is twice extracted with CHCl₃ and the organic phase is then washed with aqueous saturated NaHCO₃ solution. The organic phase is dried (MgSO₄), filtered, concentrated in vacuo and the resulting residue is purified by preparative HPLC to afford the desired product as a yellowish solid: ¹H NMR (300 MHz, d₃-DMSO) δ 8.64 (s, 1H), 7.64-7.52 (m, 1H), 7.38-7.24 (m, 5H), 7.14-7.08 (m, 1H), 6.57 (s, 1H), 5.95 (s, 1H), 4.31 (bd s, NH), 3.85 (q, J=7.2 Hz, 2H), 3.34 (m, 1H), 1.04 (s, 9H), 0.93 (t, J=7.2 Hz); ESI⁺ MS: m/z (rel intensity) 541.0 (100, M⁺+H).

The compounds which comprise Category III of the present invention relate to 2-amino-6-[substituted or unsubstituted]acyl-7-[substituted or unsubstituted]heteroaryl or heterocyclic pyrrolo[2,3-d]pyrimidines having the formula:

wherein R, R¹, and R² are defined herein below in Table V.

TABLE V No. R R¹ R² 161 2-hydroxy-1,2- 4-fluorophenyl 2,5-dimethyl-2H- dimethylpropyl pyrazol-3-yl 162 2-methoxy-1-methylethyl 4-fluorophenyl 2,5-dimethyl-2H- pyrazol-3-yl 163 1-methylpropyl 4-fluorophenyl 2,5-dimethyl-2H- pyrazol-3-yl 164 N,N-dimethylamino 4-fluorophenyl 2,5-dimethyl-2H- pyrazol-3-yl 165 2-cyano-1,2-dimethylpropyl 4-fluorophenyl 2,5-dimethyl-2H- pyrazol-3-yl 166 2-hydroxy-1,2- 4-fluorophenyl 1H-imidazol-2-yl dimethylpropyl 167 2-methoxy-1-methylethyl 4-fluorophenyl 1H-imidazol-2-yl 168 1-methylpropyl 4-fluorophenyl 1H-imidazol-2-yl 169 N,N-dimethylamino 4-fluorophenyl 1H-imidazol-2-yl 170 2-cyano-1,2-dimethylpropyl 4-fluorophenyl 1H-imidazol-2-yl 171 2-hydroxy-1,2- 4-fluorophenyl 1H-imidazol-4-yl dimethylpropyl 172 2-methoxy-1-methylethyl 4-fluorophenyl 1H-imidazol-4-yl 173 1-methylpropyl 4-fluorophenyl 1H-imidazol-4-yl 174 N,N-dimethylamino 4-fluorophenyl 1H-imidazol-4-yl 175 2-cyano-1,2-dimethylpropyl 4-fluorophenyl 1H-imidazol-4-yl 176 2-hydroxy-1,2- 4-fluorophenyl pyridin-4-yl dimethylpropyl 177 2-methoxy-1-methylethyl 4-fluorophenyl pyridin-4-yl 178 1-methylpropyl 4-fluorophenyl pyridin-4-yl 179 N,N-dimethylamino 4-fluorophenyl pyridin-4-yl 180 2-cyano-1,2-dimethylpropyl 4-fluorophenyl pyridin-4-yl 181 2-hydroxy-1,2- 2-chlorophenyl pyridin-3-yl dimethylpropyl 182 2-methoxy-1-methylethyl 2-chlorophenyl pyridin-3-yl 183 1-methylpropyl 2-chlorophenyl pyridin-3-yl 184 N,N-dimethylamino 2-chlorophenyl pyridin-3-yl 185 2-cyano-1,2-dimethylpropyl 2-chlorophenyl pyridin-3-yl 186 2-hydroxy-1,2- 2-chlorophenyl pyridin-2-yl dimethylpropyl 187 2-methoxy-1-methylethyl 2-chlorophenyl pyridin-2-yl 188 1-methylpropyl 2-chlorophenyl pyridin-2-yl 189 N,N-dimethylamino 2-chlorophenyl pyridin-2-yl 190 2-cyano-1,2-dimethylpropyl 2-chlorophenyl pyridin-2-yl 191 2-hydroxy-1,2- 2-chlorophenyl 2,5-dimethyl-2H- dimethylpropyl pyrazol-3-yl 192 2-methoxy-1-methylethyl 2-chlorophenyl 2,5-dimethyl-2H- pyrazol-3-yl 193 1-methylpropyl 2-chlorophenyl 2,5-dimethyl-2H- pyrazol-3-yl 194 N,N-dimethylamino 2-chlorophenyl 2,5-dimethyl-2H- pyrazol-3-yl 195 2-cyano-1,2-dimethylpropyl 2-chlorophenyl 2,5-dimethyl-2H- pyrazol-3-yl 196 2-hydroxy-1,2- 2-chlorophenyl 1H-imidazol-2-yl dimethylpropyl 197 2-methoxy-1-methylethyl 2-chlorophenyl 1H-imidazol-2-yl 198 1-methylpropyl 2-chlorophenyl 1H-imidazol-2-yl 199 N,N-dimethylamino 2-chlorophenyl 1H-imidazol-2-yl 200 2-cyano-1,2-dimethylpropyl 2-chlorophenyl 1H-imidazol-2-yl 201 2-hydroxy-1,2- 2-chlorophenyl 1H-imidazol-4-yl dimethylpropyl 202 2-methoxy-1-methylethyl 2-chlorophenyl 1H-imidazol-4-yl 203 1-methylpropyl 2-chlorophenyl 1H-imidazol-4-yl 204 N,N-dimethylamino 2-chlorophenyl 1H-imidazol-4-yl 205 2-cyano-1,2-dimethylpropyl 2-chlorophenyl 1H-imidazol-4-yl 206 2-hydroxy-1,2- 2-chlorophenyl pyridin-4-yl dimethylpropyl 207 2-methoxy-1-methylethyl 2-chlorophenyl pyridin-4-yl 208 1-methylpropyl 2-chlorophenyl pyridin-4-yl 209 N,N-dimethylamino 2-chlorophenyl pyridin-4-yl 210 2-cyano-1,2-dimethylpropyl 2-chlorophenyl pyridin-4-yl

The compounds which comprise the first aspect of Category III can be prepared by the process described herein below and outlined in Scheme VII.

EXAMPLE 7 (2-Chlorophenyl)-[7-(2,5-dimethyl-2H-pyrazol-3-yl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone (21)

Preparation of 4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (16): To a solution of 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (4.6 g, 19.6 mmol) in ethanol (90 mL) is added 5-amino-1,3-dimethylpyrazole (4.4 g, 39.2 mmol). The mixture is heated for 22 hours at 80° C. The reaction is cooled to room temp and concentrated in vacuo. The solid which remains is dissolved in CHCl₃ and washed with aqueous saturated NaHCO₃ solution. The organic phase is dried (MgSO₄), filtered and concentrated in vacuo and the resulting residue is purified over silica (50% EtOAc//hexanes, followed by 100% EtOAc) to afford 4.8 g of the desired product: ¹H NMR (300 MHz, CDCl₃) δ10.29 (s, NH), 8.82 (s, 1H), 6.30 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 3.77 (s, 3H), 2.53 (s, 3H), 2.30 (s, 3H), 1.45 (t, J=7.2 Hz, 3H); ESI⁺ MS: m/z (rel intensity) 308.0 (100, M⁺+H).

Preparation of [4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidin-5-yl]-methanol (17): To a cold (0° C.) solution of 4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester, 16, (2.0 g, 6.5 mmol) in THF (30 mL) is added dropwise lithium aluminum hydride (10.4 mL of IM solution in THF, 10.4 mmol). The reaction is stirred at 0° C. for 5 minutes, then the ice bath is removed and the mixture allowed to stir for 45 minutes at room temperature. The reaction is re-cooled to 0° C., and H₂O (0.4 mL) added dropwise to the mixture. After stirring 10 min at 0° C., NaOH solution (0.4 mL of 2N solution) is added dropwise. After stirring an additional 10 min at 0° C., H₂O (1.2 mL) is added to the mixture, and the mixture stirred at room temperature for 15 minutes. The resulting mixture dried (MgSO₄), filtered and concentrated in vacuo. The resulting residue is purified over silica (5% MeOH//chloroform) to afford 1.0 g of the desired product: ¹H NMR (300 MHz, CDCl₃) δ 8.22 (s, NH), 7.89 (s, 1H), 6.22 (s, 1H), 4.72 (s, 2H), 3.68 (s, 3H), 2.47 (s, 3H), 2.26 (s, 3H); ESI⁺ MS: m/z (rel intensity) 266.0 (100, M⁺+H).

Preparation of 4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (18): To a solution of [4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidin-5-yl]-methanol, 17, (0.97 g, 3.66 mmol) in CH₂Cl₂/THF (35 mL of 1:1 mixture) is added manganese (IV) oxide (2.54 g, 29.28 mmol). After stirring the suspension at room temperature for 43 hours, the mixture is filtered through celite, and washed with CH₂Cl₂. The filtrate is concentrated in vacuo and the resulting residue is purified over silica (5% MeOH/chloroform) to afford 0.52 g of the desired product: ¹H NMR (300 MHz, CDCl₃) δ 8.22 (s, NH), 10.58 (s, NH), 9,86 (s, 1H), 8.54 (s, 1H), 6.36 (s, 1H), 3.81 (s, 3H), 2.58 (s, 3H), 2.30 (s, 3H); ESI⁺ MS: m/z (rel intensity) 264.0 (100, M⁺+H).

Preparation of (2-chlorophenyl)-[7-(2,5-dimethyl-2H-pyrazol-3-yl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone (19): To a solution of 4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde, 18, (0.25 g, 0.95 mmol) in DMF (4 mL) is added 2-bromo-1-(2-chloro-phenyl)-ethanone (0.33 g, 1.42 mmol) and potassium carbonate (0.26 g, 1.90 mmol). The reaction mixture is stirred at room temp for 21 hours after which the reaction solution is diluted with EtOAc and washed three times with aqueous saturated NH₄Cl. The organic phase is washed with brine, dried (MgSO₄), filtered, concentrated in vacuo and the resulting residue is dissolved in DMF (6 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL, 1.90 mmol) is added to the reaction. After stirring the reaction at room temp for 3 hours, the mixture is diluted with aqueous saturated NH₄Cl solution and extracted with EtOAc. The organic phase is washed with brine, dried (MgSO₄), filtered, concentrated in vacuo, and the resulting residue is purified over silica (33% EtOAc//hexanes) to afford 0.14 g of the desired product: ¹H NMR (300 MHz, CDCl₃) δ 8.92 (s, 1H), 7.52-7.35 (m, 4H), 7.00 (s, 1H), 6.14 (s, 1H), 3.67 (s, 3H), 2.55 (s, 3H), 2.37 (s, 3H); ESI⁺ MS: m/z (rel intensity) 398.0 (100, M⁺+H).

Preparation of (2-chlorophenyl)-[7-(2,5-dimethyl-2H-pyrazol-3-yl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone (20): To a solution of (2-chloro-phenyl)-[7-(2,5-dimethyl-2H-pyrazol-3-yl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 19, (0.13 g, 0.34 mmol) in THF:methanol (4 mL of 1:1 mixture) is added dropwise a solution of Oxone® (potassium peroxymonosulfate) (0.73 g, 1.19 mmol) in H₂O (4 mL). After stirring the reaction for 1 hour at room temperature, the solution is poured into aqueous saturated NaHCO₃. The aqueous phase is twice extracted with CHCl₃ and the combined organic phases are dried (MgSO₄), filtered and concentrated in vacuo to afford 0.12 g of the desired product which is used without further purification.

Preparation of (2-chlorophenyl)-[7-(2,5-dimethyl-2H-pyrazol-3-yl)-2-(N,N-dimethyl-N′-methyl-hydrazino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone (21): To a solution of (2-chloro-phenyl)-[7-(2,5-dimethyl-2H-pyrazol-3-yl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone, 20, (0.11 g, 0.29 mmol) in 1-methyl-2-pyrrolidinone (1 mL) is added 1,1-dimethylhydrazine (0.05 mL, 0.58 mmol). The reaction mixture is heated to 90° C. for 2 hours. The mixture is diluted with H₂O and extracted with EtOAc. The organic phase is twice washed with brine, dried (MgSO₄), filtered and concentrated in vacuo with the resulting residue purified over silica (5% MeOH//CHCl₃) to afford 67 mg of the desired product: ¹H NMR (300 MHz, CDCl₃) □8.85 (s, 1H), 7.49-7.36 (m, 4H), 6.90 (s, 1H), 6.14 (s, 1H), 6.03 (s, NH), 3.65 (s, 3H), 2.69 (s, 6H), 2.36 (s, 3H); ESI⁺ MS: m/z (rel intensity) 410.1 (100, M⁺+H).

The following are non-limiting examples of this aspect of Category III.

(2-Chlorophenyl)-[2-(N,N-dimethyl-N′-methylhydrazino)-7-(5-methyl-isoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.85 (s, 1H), 7.57-7.36 (m, 4H), 6.91 (s, 1H), 6.37 (s, 1H), 6.25 (bd s, NH), 2.73 (s, 6H), 2.57 (s, 3H); ESI⁺ MS: m/z (rel intensity) 410.1 (100, M⁺+H).

(2-Chlorophenyl)-[2-(2-hydroxy-1,2-dimethyl-propylamino)-7-(5-methyl-isoxazol-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-methanone: ¹H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H), 7.55-7.35 (m, 4H), 6.86 (s, 1H), 6.34 (s, 1H), 5.69 (bd s, NH), 4.15-4.05 (m, 1H), 2.66 (s, 3H), 1.29 (s, 3H), 1.24 (s, 6H); ESI⁺ MS: m/z (rel intensity) 440.1 (100, M⁺+H).

The compounds which comprise Category IV of the present invention have the formula:

the first aspect of which relates to 2-[substituted or unsubstituted]alkyl, aryl, or heterocyclic amino-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines-6-carboxylic acid [substituted or unsubstituted]aryl-amides having the formula:

wherein R, R¹, and R² are defined herein below in Table VI

TABLE VI No. R R¹ R² 211 2-methyl-2-hydroxy-1-(S)- 4-fluorophenyl 4-fluorophenyl methylpropyl 212 2-methoxy-1-(S)- 4-fluorophenyl 4-fluorophenyl methylethyl 213 2-methyl-2-cyano-1-(S)- 4-fluorophenyl 4-fluorophenyl methylpropyl 214 1-(S)-methylpropyl 4-fluorophenyl 4-fluorophenyl 215 N,N-dimethylamino 4-fluorophenyl 4-fluorophenyl 216 piperidin-1-yl 4-fluorophenyl 4-fluorophenyl 217 morpholin-4-yl 4-fluorophenyl 4-fluorophenyl 218 pyran-4-yl 4-fluorophenyl 4-fluorophenyl 219 phenyl 4-fluorophenyl 4-fluorophenyl 220 2,6-difluorophenyl 4-fluorophenyl 4-fluorophenyl 221 2-methyl-2-hydroxy-1-(S)- 4-fluorophenyl 2,6-difluorophenyl methylpropyl 222 2-methoxy-1-(S)- 4-fluorophenyl 2,6-difluorophenyl methylethyl 223 2-methyl-2-cyano-1-(S)- 4-fluorophenyl 2,6-difluorophenyl methylpropyl 224 1-(S)-methylpropyl 4-fluorophenyl 2,6-difluorophenyl 225 N,N-dimethylamino 4-fluorophenyl 2,6-difluorophenyl 226 piperidin-1-yl 4-fluorophenyl 2,6-difluorophenyl 227 morpholin-4-yl 4-fluorophenyl 2,6-difluorophenyl 228 pyran-4-yl 4-fluorophenyl 2,6-difluorophenyl 229 phenyl 4-fluorophenyl 2,6-difluorophenyl 230 2,6-difluorophenyl 4-fluorophenyl 2,6-difluorophenyl 231 2-methyl-2-hydroxy-1-(S)- 2-chlorophenyl 4-fluorophenyl methylpropyl 232 2-methoxy-1-(S)- 2-chlorophenyl 4-fluorophenyl methylethyl 233 2-methyl-2-cyano-1-(S)- 2-chlorophenyl 4-fluorophenyl methylpropyl 234 1-(S)-methylpropyl 2-chlorophenyl 4-fluorophenyl 235 N,N-dimethylamino 2-chlorophenyl 4-fluorophenyl 236 piperidin-1-yl 2-chlorophenyl 4-fluorophenyl 237 morpholin-4-yl 2-chlorophenyl 4-fluorophenyl 238 pyran-4-yl 2-chlorophenyl 4-fluorophenyl 239 phenyl 2-chlorophenyl 4-fluorophenyl 240 2,6-difluorophenyl 2-chlorophenyl 4-fluorophenyl 241 2-methyl-2-hydroxy-1-(S)- 2-chlorophenyl 4-fluorophenyl methylpropyl 242 2-methoxy-1-(S)- 2-chlorophenyl 2,6-difluorophenyl methylethyl 243 2-methyl-2-cyano-1-(S)- 2-chlorophenyl 2,6-difluorophenyl methylpropyl 244 1-(S)-methylpropyl 2-chlorophenyl 2,6-difluorophenyl 245 N,N-dimethylamino 2-chlorophenyl 2,6-difluorophenyl 246 piperidin-1-yl 2-chlorophenyl 2,6-difluorophenyl 247 morpholin-4-yl 2-chlorophenyl 2,6-difluorophenyl 248 pyran-4-yl 2-chlorophenyl 2,6-difluorophenyl 249 phenyl 2-chlorophenyl 2,6-difluorophenyl 250 2,6-difluorophenyl 2-chlorophenyl 2,6-difluorophenyl

The compounds which comprise the first aspect of Category IV can be prepared by the procedure described herein below and outline in Scheme VIII.

EXAMPLE 8 7-(4-Fluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chlorophenyl)-amide (28)

Starting material, intermediate 18, can be prepared in the same manner as intermediate 2, described herein above in Scheme I, by substituting 4-fluoroaniline for 2,6-difluoroaniline.

Preparation of 7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester (23): To a solution of 4-(4-fluorophenylamino)-2-methyl-sulfanyl-pyrimidine-5-carbaldehyde, 22, (26.3 g, 100.0 mmol) in dimethylformamide (450 mL) is added potassium carbonate (41.5 g, 300.2 mmol) and methyl bromoacetate (14.7 mL, 150.0 mmole). The mixture is allowed to stir at ambient temperature for 19 hours. The reaction is then diluted with H₂O and extracted three times with EtOAc. The organic layer is washed with brine, dried (MgSO₄), filtered, and concentrated in vacuo. The resulting residue is purified over silica (10% to 40% EtOAc/hexanes) to afford 6.9 g of the desired product as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 8.94 (s, 1H), 7.42 (s, 1H), 7.36 (dd, J=8.2, 5.9 Hz, 2H), 7.22 (t, J=8.7 Hz, 1H), 3.82 (s, 3H), 2.49 (s, 3H); ESI⁺ MS: m/z (rel intensity) 317.9 (100, M⁺+H).

Preparation of 7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (24): To a solution of 7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester, 23, (3.1 g, 9.7 mmol) in THF (40 mL) is added a solution of NaOH (3.9 g, 97.0 mmol) in water (30 mL). The reaction is allowed to stir for 3 hours at room temperature before the mixture is diluted with H₂O and extracted three times with EtOAc. The aqueous phase is acidified slowly to pH 1-2 with conc. HCl and then extracted three times with EtOAc. The combined organic phases are rinsed with brine, dried (MgSO₄), filtered, and concentrated in vacuo to afford 2.5 g of the desired product which was used without further purification: ¹H NMR (300 MHz, d₆-DMSO) δ 9.06 (s, 1H), 7.44 (s, 1H), 7.52 (dd, J=8.2, 5.9 Hz, 2H), 7.38 (t, J=8.7 Hz, 1H), 2.44 (s, 3H); ESI⁺ MS: m/z (rel intensity) 304.0 (100, M⁺+H).

Preparation of 7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonyl chloride (25): To a cold (0° C.) solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, 24, (4.7 g, 15.5 mmol) in dichloromethane (100 mL) is added DMF (0.5 mL) followed by dropwise addition of oxalyl chloride (2.7 mL, 31.1 mmol). The mixture is allowed to slowly warm to room temperature over a period of 3 hours. The reaction mixture is concentrated in vacuo and can be dried azeotropically with toluene to afford 4.7 g of the desired product, which is used without further purification: ¹H NMR (300 MHz, CDCl₃) δ 9.38 (s, 1H), 8.04 (s, 1H), 7.40-7.20 (m, 4H), 2.58 (s, 3H); ESI⁺ MS: m/z (rel intensity) 322.0 (100, M⁺+H).

Preparation of 7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chlorophenyl)-amide (26): To a solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonyl chloride, 25, (0.57 g, 1.77 mmol) in dichloromethane (10 mL) is added 2-chloroaniline (0.28 mL, 2.66 mmol) and triethylamine (0.74 mL, 5.3 mmol). The mixture is allowed to stir at ambient temperature for 16 hours. The reaction was diluted with H₂O and extracted three times with EtOAc. The combined organic phases are rinsed with brine, dried (MgSO₄), filtered and concentrated in vacuo wherein the crude residue is purified over silica (5% to 40% EtOAc/hexanes) to afford 365 mg the desired product: ¹H NMR (300 MHz, CDCl₃) δ 9.00 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 8.32 (br s, NH), 7.55-7.50 (m, 2H), 7.42 (d, J=8.2 Hz, 1H), 7.36-7.20 (m, 3H), 7.12 (t, J=8.7 Hz, 1H), 2.49 (s, 3H); ESI⁺ MS: m/z (rel intensity) 413.0 (100, M⁺+H).

Preparation of 7-(4-fluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chlorophenyl)-amide (27): To a cold (0° C.) solution of 7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chlorophenyl)-amide, 26, (0.37 g, 0.88 mmol) in CH₂Cl₂ (15 mL) is added 3-chloroperoxybenzoic acid (0.64 g of 77% mixture, 2.21 mmol). After allowing the mixture to warm to room temp over a period of 2 hours, the mixture is diluted with EtOAc and washed with saturated NaHCO₃ solution (4×) and brine. The organic phase is dried (MgSO₄), filtered, and concentrated in vacuo to afford 360 mg of the desired product, which is used without further purification: ¹H NMR (300 MHz, CDCl₃) δ 9.38 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 8.32 (br s, NH), 7.55-7.50 (m, 2H), 7.42 (d, J=8.2 Hz, 1H), 7.36-7.20 (m, 3H), 7.12 (t, J=8.7 Hz, 1H), 3.38 (s, 3H); ESI⁺ MS: m/z (rel intensity) 445.0 (100, M⁺+H).

Preparation of 7-(4-fluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chlorophenyl)-amide (28): To a solution of 7-(4-fluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chloro-phenyl)-amide, 27, (0.11 g, 0.25 mmol) in N-methyl-pyrrolidinone (3 mL) is added diisopropylethylamine (0.22 mL, 1.28 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.11 g, 0.77 mmol). The mixture is heated to 140° C. for 4 hours and the resulting solution purified by preparative HPLC to afford the desired product as a yellowish solid: ¹H NMR (300 MHz, CDCl₃) δ 8.58 (s, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.23 (s, 1H), 7.45-7.40 (m, 3H), 7.32-7.22 (m, 3H), 7.13 (t, J=8.1 Hz, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI⁺ MS: m/z (rel intensity) 468.0.0 (100, M⁺+H).

The following are non-limiting examples of compounds according to aspect one of Category IV.

7-(4-Fluorophenyl)-2-phenoxy-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chlorophenyl)-amide, (xx): ¹H NMR (300 MHz, CDCl₃) δ 8.96 (s, 1H), 8.41 (d, J=8.2 Hz, 1H), 8.27 (s, 1H), 7.50-7.39 (m, 5H), 7.34-7.18 (m, 5H), 7.12 (t, J=8.2 Hz, 2H); ESI⁺ MS: m/z (rel intensity) 458.9 (100, M⁺+H).

2-(2,6-Difluorophenylamino)-7-(4-fluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (2-chlorophenyl)-amide, (xx): ¹H NMR (300 MHz, CDCl₃) δ 8.84 (s, 1H), 8.41 (d, J=8.5 Hz, 1H), 8.24 (s, 1H), 7.48-7.40 (m, 3H), 7.32-7.16 (m, 4H), 7.10 (t, J=6.0 Hz, 2H); ESI⁺ MS: m/z (rel intensity) 493.9 (100, M⁺+H).

The second aspect of Category IV relates to 2-[substituted or unsubstituted]alkyl, aryl, or heterocyclic amino-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines-6-[substituted or unsubstituted]aryl-ethanone having the formula:

wherein R, R¹, and R² are defined herein below in Table VII

TABLE VII No. R R¹ R² 251 2-methyl-2-hydroxy-1- 2,6-dichlorophenyl 4-fluorophenyl (S)-methylpropyl 252 2-methoxy-1-(S)- 2,6-dichlorophenyl 4-fluorophenyl methylethyl 253 2-methyl-2-cyano-1- 2,6-dichlorophenyl 4-fluorophenyl (S)-methylpropyl 254 1-(S)-methylpropyl 2,6-dichlorophenyl 4-fluorophenyl 255 N,N-dimethylamino 2,6-dichlorophenyl 4-fluorophenyl 256 piperidin-1-yl 2,6-dichlorophenyl 4-fluorophenyl 257 morpholin-4-yl 2,6-dichlorophenyl 4-fluorophenyl 258 pyran-4-yl 2,6-dichlorophenyl 4-fluorophenyl 259 phenyl 2,6-dichlorophenyl 4-fluorophenyl 260 2,6-difluorophenyl 2,6-dichlorophenyl 4-fluorophenyl 261 2-methyl-2-hydroxy-1- 2,6-dichlorophenyl 2,6-difluorophenyl (S)-methylpropyl 262 2-methoxy-1-(S)- 2,6-dichlorophenyl 2,6-difluorophenyl methylethyl 263 2-methyl-2-cyano-1- 2,6-dichlorophenyl 2,6-difluorophenyl (S)-methylpropyl 264 1-(S)-methylpropyl 2,6-dichlorophenyl 2,6-difluorophenyl 265 N,N-dimethylamino 2,6-dichlorophenyl 2,6-difluorophenyl 266 piperidin-1-yl 2,6-dichlorophenyl 2,6-difluorophenyl 267 morpholin-4-yl 2,6-dichlorophenyl 2,6-difluorophenyl 268 pyran-4-yl 2,6-dichlorophenyl 2,6-difluorophenyl 269 phenyl 2,6-dichlorophenyl 2,6-difluorophenyl 270 2,6-difluorophenyl 2,6-dichlorophenyl 2,6-difluorophenyl 271 2-methyl-2-hydroxy-1- 2-chlorophenyl 4-fluorophenyl (S)-methylpropyl 272 2-methoxy-1-(S)- 2-chlorophenyl 4-fluorophenyl methylethyl 273 2-methyl-2-cyano-1- 2-chlorophenyl 4-fluorophenyl (S)-methylpropyl 274 1-(S)-methylpropyl 2-chlorophenyl 4-fluorophenyl 275 N,N-dimethylamino 2-chlorophenyl 4-fluorophenyl 276 piperidin-1-yl 2-chlorophenyl 4-fluorophenyl 277 morpholin-4-yl 2-chlorophenyl 4-fluorophenyl 278 pyran-4-yl 2-chlorophenyl 4-fluorophenyl 279 phenyl 2-chlorophenyl 4-fluorophenyl 280 2,6-difluorophenyl 2-chlorophenyl 4-fluorophenyl 281 2-methyl-2-hydroxy-1- 2-chlorophenyl 4-fluorophenyl (S)-methylpropyl 282 2-methoxy-1-(S)- 2-chlorophenyl 2,6-difluorophenyl methylethyl 283 2-methyl-2-cyano-1- 2-chlorophenyl 2,6-difluorophenyl (S)-methylpropyl 284 1-(S)-methylpropyl 2-chlorophenyl 2,6-difluorophenyl 285 N,N-dimethylamino 2-chlorophenyl 2,6-difluorophenyl 286 piperidin-1-yl 2-chlorophenyl 2,6-difluorophenyl 287 morpholin-4-yl 2-chlorophenyl 2,6-difluorophenyl 288 pyran-4-yl 2-chlorophenyl 2,6-difluorophenyl 289 phenyl 2-chlorophenyl 2,6-difluorophenyl 290 2,6-difluorophenyl 2-chlorophenyl 2,6-difluorophenyl

The compounds which comprise the second aspect of Category IV can be prepared by the procedure described herein below and outline in Scheme IX.

EXAMPLE 9 2-(2-Chlorophenyl)-1-[7-(4-fluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone (32)

Preparation of 7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methoxy-methyl-amide (29): To a solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonyl chloride, 25, (1.02 g, 3.15 mmol) in CH₂Cl₂ (20 mL) is added N,O-dimethylhydroxylamine hydrochloride salt (0.37 g, 3.80 mmol) and triethylamine (1.32 mL, 9.50 mmol). The mixture is allowed to stir at room temperature for 16 hours. The reaction is diluted with H₂O and extracted three times with EtOAc and the combined organic layers are washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. The crude residue is purified over silica (5% to 40% EtOAc/hexanes) to afford 660 mg of the desired product: ¹H NMR (300 MHz, CDCl₃) δ 8.90 (s, 1H), 7.44 (dd, J=8.4, 5.9 Hz, 2H), 7.22 (dd, J=8.4, 5.9 Hz, 2H), 7.10 (s, 1H), 3.62 (s, 3H), 3.26 (s, 3H), 2.54 (s, 3H); ESI⁺ MS: m/z (rel intensity) 347.0 (100, M⁺+H).

Preparation of 2-(2-chlorophenyl)-1-[7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone (30): To a round bottom flask equipped with a condenser is added Mg powder (0.35 g, 0.02 mmol) and diethyl ether (10 mL). 2-Chlorobenzyl bromide (0.10 mL, 0.76 mmol) and a catalytic amount of 1,2-dibromoethane (5 μL) is added to the reaction mixture. After an initial exotherm, the reaction solution develops a yellow color. 7-(4-Fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methoxy-methyl-amide, 29, (0.22 g, 0.63 mmol) is dissolved in THF (10 mL) and the Grignard reagent is then carefully transferred dropwise using a cannula using nitrogen to initiate and continue the transfer. The mixture is allowed to stir at room temperature for 2 hours after which the magnesium is removed by filtration and the filtrate concentrated in vacuo. The residue is purified by preparative HPLC to afford 64 mg of the desired product as a pale colored solid: ¹H NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 7.60 (s, 1H), 7.42-7.38 (m, 1H), 7.37-7.22 (m, 5H), 7.18 (t, J=8.7 Hz, 2H), 4.40 (s, 2H), 2.44 (s, 3H); ESI⁺ MS: m/z (rel intensity) 411.9 (100, M⁺+H).

Preparation of 2-(2-chlorophenyl)-1-[7-(4-fluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone (31): To a cold (0° C.) solution of 2-(2-chlorophenyl)-1-[7-(4-fluorophenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone, 30, (0.06 g, 0.15 mmol) in CH₂Cl₂ (6 mL) is added 3-chloroperoxybenzoic acid (0.07 g of 77% mixture, 0.39 mmol). The mixture is allowed to warm to room temperature over a period of 2 hours. The mixture is diluted with EtOAc, washed with aqueous saturated NaHCO₃ solution, brine, and the organic phase is dried (MgSO₄), filtered, and concentrated in vacuo to afford 73 mg of the desired product which was used without further purification: ¹H NMR (300 MHz, CDCl₃) δ 9.38 (s, 1H), 8.20 (s, 1H), 7.68 (s, 1H), 7.42-7.38 (m, 1H), 7.37-7.22 (m, 5H), 7.18 (t, J=8.7 Hz, 2H), 4.44 (s, 2H), 3.32 (s, 3H); ESI⁺ MS: m/z (rel intensity) 443.9 (100, M⁺+H).

Preparation of 2-(2-chlorophenyl)-1-[7-(4-fluorophenyl)-2-(2-hydroxy-1,2-dimethyl-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone (32): To a solution of 2-(2-chloro-phenyl)-1-[7-(4-fluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone, 31, (0.036 g, 0.080 mmol) in N-methylpyrrolidinone (2 mL) is added diisopropylethylamine (0.071 mL, 0.410 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.035 g, 0.240 mmol). The mixture is heated to 120° C. for 4 hours. The reaction crude product is then purified by preparative HPLC to afford the desired product as a yellowish solid: ¹H NMR (300 MHz, CDCl₃) δ 8.60 (s, 1H), 7.54 (s, 1H), 7.42-7.38 (m, 1H), 7.32-7.10 (m, 7H), 4.36 (s, 2H), 3.92-3.82 (m, 1H), 1.26 (d, J=9.1 Hz, 6H), 1.20 (d, J=6.8 Hz, 3H); ESI⁺ MS: m/z (rel intensity) 467.0 (100, M⁺+H).

The following are non-limiting examples of compounds according to the second aspect of Category IV.

2-(2-Chlorophenyl)-1-[7-(4-fluorophenyl)-2-(1-phenylethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone: ¹H NMR (300 MHz, CDCl₃) δ 10.02 (br d, NH), 8.62 (s, 1H), 7.50 (s, 1H), 7.42-7.37 (m, 1H), 7.30-7.14 (m, 10H), 7.13-7.05 (m, 2H), 4.82 (q, br, 1H), 4.30 (s, 2H), 1.60 (d, J=7.0 Hz, 3H); ESI⁺ MS: m/z (rel intensity) 485.0 (100, M⁺+H).

The third aspect of Category IV relates to 2-[substituted or unsubstituted]alkyl, aryl, or heterocyclic amino-7-[substituted or unsubstituted]aryl pyrrolo[2,3-d]pyrimidines-6-[substituted or unsubstituted]aryl or alkyl-sulfonyl compounds having the formula:

wherein R, R¹, and R² are defined herein below in Table VIII

TABLE VIII No. R R¹ R² 291 2-methyl-2-hydroxy-1- 2,6-dichlorophenyl 4-fluorophenyl (S)-methylpropyl 292 2-methoxy-1-(S)- 2,6-dichlorophenyl 4-fluorophenyl methylethyl 293 2-methyl-2-cyano-1- 2,6-dichlorophenyl 4-fluorophenyl (S)-methylpropyl 294 1-(S)-methylpropyl 2,6-dichlorophenyl 4-fluorophenyl 295 N,N-dimethylamino 2,6-dichlorophenyl 4-fluorophenyl 296 piperidin-1-yl 2,6-dichlorophenyl 4-fluorophenyl 297 morpholin-4-yl 2,6-dichlorophenyl 4-fluorophenyl 298 pyran-4-yl 2,6-dichlorophenyl 4-fluorophenyl 299 phenyl 2,6-dichlorophenyl 4-fluorophenyl 300 2,6-difluorophenyl 2,6-dichlorophenyl 4-fluorophenyl 301 2-methyl-2-hydroxy-1- 2,6-dichlorophenyl 2,6-difluorophenyl (S)-methylpropyl 302 2-methoxy-1-(S)- 2,6-dichlorophenyl 2,6-difluorophenyl methylethyl 303 2-methyl-2-cyano-1- 2,6-dichlorophenyl 2,6-difluorophenyl (S)-methylpropyl 304 1-(S)-methylpropyl 2,6-dichlorophenyl 2,6-difluorophenyl 305 N,N-dimethylamino 2,6-dichlorophenyl 2,6-difluorophenyl 306 piperidin-1-yl 2,6-dichlorophenyl 2,6-difluorophenyl 307 morpholin-4-yl 2,6-dichlorophenyl 2,6-difluorophenyl 308 pyran-4-yl 2,6-dichlorophenyl 2,6-difluorophenyl 309 phenyl 2,6-dichlorophenyl 2,6-difluorophenyl 310 2,6-difluorophenyl 2,6-dichlorophenyl 2,6-difluorophenyl 311 2-methyl-2-hydroxy-1- 2-chlorophenyl 4-fluorophenyl (S)-methylpropyl 312 2-methoxy-1-(S)- 2-chlorophenyl 4-fluorophenyl methylethyl 313 2-methyl-2-cyano-1- 2-chlorophenyl 4-fluorophenyl (S)-methylpropyl 314 1-(S)-methylpropyl 2-chlorophenyl 4-fluorophenyl 315 N,N-dimethylamino 2-chlorophenyl 4-fluorophenyl 316 piperidin-1-yl 2-chlorophenyl 4-fluorophenyl 317 morpholin-4-yl 2-chlorophenyl 4-fluorophenyl 318 pyran-4-yl 2-chlorophenyl 4-fluorophenyl 319 phenyl 2-chlorophenyl 4-fluorophenyl 320 2,6-difluorophenyl 2-chlorophenyl 4-fluorophenyl 321 2-methyl-2-hydroxy-1- 2-chlorophenyl 4-fluorophenyl (S)-methylpropyl 322 2-methoxy-1-(S)- 2-chlorophenyl 2,6-difluorophenyl methylethyl 323 2-methyl-2-cyano-1- 2-chlorophenyl 2,6-difluorophenyl (S)-methylpropyl 324 1-(S)-methylpropyl 2-chlorophenyl 2,6-difluorophenyl 325 N,N-dimethylamino 2-chlorophenyl 2,6-difluorophenyl 326 piperidin-1-yl 2-chlorophenyl 2,6-difluorophenyl 327 morpholin-4-yl 2-chlorophenyl 2,6-difluorophenyl 328 pyran-4-yl 2-chlorophenyl 2,6-difluorophenyl 329 phenyl 2-chlorophenyl 2,6-difluorophenyl 330 2,6-difluorophenyl 2-chlorophenyl 2,6-difluorophenyl

The compounds which comprise the third aspect of Category IV can be prepared by the procedure described herein below and outlined in Scheme X.

EXAMPLE 10 [6-Benzenesulfonyl-7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-morpholin-4-yl-amine (35)

Preparation of 6-benzenesulfonyl-7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine (33): To a solution of 4-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde, 22, (1.18 g, 4.48 mmol) in DMF (20 mL) is added potassium carbonate (1.86 g, 13.4 mmol) and bromomethanesulfonyl benzene (1.58 g, 6.70 mmol). The mixture is stirred at room temperature for 19 hour then diluted with H₂O and the resulting mixture is extracted with EtOAc. The combined organic phases are washed with brine, dried (MgSO₄), filtered, concentrated in vacuo, and the crude residue is purified over silica (10% to 40% EtOAc/hexanes) to afford 480 g of the desired product as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.12 (s, 1H), 7.98 (s, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.70 (dd, J=8.8, 5.5 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.28-7.20 (m, 3H), 2.58 (s, 3H); ESI⁺ MS: m/z (rel intensity) 399.8 (100, M⁺+H).

Preparation of 6-benzenesulfonyl-7-(4-fluorophenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidine (34): To a cold (0° C.) solution of 6-benzenesulfonyl-7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine, 33, (0.24 g, 0.61 mmol) in CH₂Cl₂ (10 mL) is added 3-chloroperoxybenzoic acid (77%, 0.37 g, 1.51 mmol). After stirring the mixture at room temperature for 2 hours, the reaction mixture is diluted with EtOAc and washed with aqueous saturated NaHCO₃ solution, brine, dried (MgSO₄), filtered, and concentrated in vacuo to afford 192 mg of the desired product: ¹H NMR (300 MHz, CDCl₃) δ 9.52 (s, 1H), 8.32 (s, 1H), 8.06 (d, J=8.2 Hz, 2H), 7.70-7.64 (m, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.42 (t, J=8.7 Hz, 1H), 7.36 (dd, J=8.8, 5.5 Hz, 2H), 3.38 (s, 3H); ESI⁺ MS: m/z (rel intensity) 431.8 (100, M⁺+H).

Preparation of [6-Benzenesulfonyl-7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-morpholin-4-yl-amine (35): 6-Benzenesulfonyl-7-(4-fluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidine, 34, (0.04 g, 0.10 mmol) in N-methylpyrrolidinone (3 mL) is added diisopropylethylamine (0.41 mL, 2.36 mmol) and 3-amino-2-methyl-butan-2-ol hydrochloride salt (0.10 g, 0.71 mmol). The mixture is heated to 90° C. for 21 hours. The product is purified by preparative HPLC to afford 50 mg of the desired product as a yellowish solid: ¹H NMR (300 MHz, d6-DMSO) δ 8.64 (s, 1H), 7.64-7.47 (m, 1H), 7.42-7.25 (m, 5H), 7.14-7.09 (m, 1H), 6.56 (s, 1H), 5.95 (s, 1H), 4.30 (s, 1H), 3.85 (q, J=7.2 Hz, 2H), 1.04 (s, 9H), 0.93 (t, J=7.2 Hz, 3H); ESI⁺ MS: m/z (rel intensity) 540.9 (100, M⁺+H).

Compounds listed and described herein above have been found in many instances to exhibit activities (IC₅₀ in the cell based assay described herein below or ones which are referenced herein) at a level below 1 micromolar (μM).

The compounds of the present invention are capable of effectively blocking the production of inflammatory cytokine production from cells, which thereby allows for the mitigation, alleviation, control, abatement, retardation, or prevention of one or more disease states or syndromes which are related to the extracellular release of one or more cytokines.

Inflammatory Disease States

Inflammatory disease states include those which are related to the following non-limiting examples:

-   -   i) Interleukin-1 (IL-1): implicated as the molecule responsible         for a large number of disease states, inter alia, rheumatoid         arthritis, osteoarthritis, as well as other disease states which         relate to connective tissue degradation.     -   ii) Cycloxygenase-2 (COX-2): inhibitors of cytokine release are         proposed as inhibitors of inducible COX-2 expression, which has         been shown to be increased by cytokines. M. K. O'Banion et al.,         Proc. Natl. Acad. Sci. U.S.A., 89, 4888 (1998).     -   iii) Tumor Necrosis Factor-α (TNF-α): This pro-inflammatory         cytokine is suggested as an important mediator in many disease         states or syndromes, inter alia, rheumatoid arthritis,         osteoarthritis, inflammatory bowel disease (IBS), septic shock,         cardiopulmonary dysfunction, acute respiratory disease, and         cachexia.

Each of the disease states or conditions which the formulator desires to treat may require differing levels or amounts of the compounds described herein to obtain a therapeutic level. The formulator can determine this amount by any of the known testing procedures known to the artisan.

The present invention further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein. One iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein. The formulator, for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present analogs over another since the compounds themselves are the active species which mitigate the disease processes described herein.

FORMULATIONS

The present invention also relates to compositions or formulations which comprise the inflammatory cytokine release-inhibiting compounds according to the present invention. In general, the compositions of the present invention comprise:

-   -   a) an effective amount of one or more 2,6,7-substituted         pyrrolo[2,3-d]pyrimidines and derivatives thereof according to         the present invention which are effective for inhibiting release         of inflammatory cytokines; and     -   b) one or more pharmaceutically acceptable excipients.

For the purposes of the present invention the term “excipient” and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

Non-limiting examples of compositions according to the present invention include:

-   -   a) from about 0.001 mg to about 1000 mg of one or more         2,6,7-substituted pyrrolo[2,3-d]pyrimidines according to the         present invention; and     -   b) one or more excipient.

Another embodiment according to the present invention relates to the following compositions:

-   -   a) from about 0.01 mg to about 100 mg of one or more         2,6,7-substituted pyrrolo[2,3-d]pyrimidines according to the         present invention; and     -   b) one or more pharmaceutical excipient.

A further embodiment according to the present invention relates to the following compositions:

-   -   a) from about 0.1 mg to about 10 mg of one or more         2,6,7-substituted pyrrolo[2,3-d]pyrimidines according to the         present invention; and     -   b) one or more pharmaceutical excipient.

The term “effective amount” as used herein means “an amount of one or more 2,6,7-substituted pyrrolo[2,3-d]pyrimidines, effective at dosages and for periods of time necessary to achieve the desired result.” An effective amount may vary according to factors known in the art, such as the disease state, age, sex, and weight of the human or animal being treated. Although particular dosage regimes may be described in examples herein, a person skilled in the art would appreciated that the dosage regime may be altered to provide optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions of the present invention can be administered as frequently as necessary to achieve a therapeutic amount.

METHOD OF USE

The present invention also relates to a method for controlling the level of one or more inflammation inducing cytokines, inter alia, interleukin-1 (IL-1), Tumor Necrosis Factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8) and thereby controlling, mediating, or abating disease states affected by the levels of extracellular inflammatory cytokines. The present method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more of the inflammatory cytokine inhibitors according to the present invention.

The present invention also relates to the use of the 2,6,7-substituted pyrrolo[2,3-d]pyrimidines according to the present invention in the manufacture of a medicament for the treatment of inflammatory cytokine related disorders. These disorders are described herein above under Inflammatory Disease States.

Because the inflammatory cytokine inhibitors of the present invention can be delivered in a manner wherein more than one site of control can be achieved, more than one disease state can be modulated at the same time. Non-limiting examples of diseases which are affected by control or inhibition of inflammatory cytokine inhibitors, thereby modulating excessive cytokine activity, include osteoarthritis, rheumatoid arthritis, diabetes, human Immunodeficiency virus (HIV) infection.

PROCEDURES

The compounds of the present invention can be evaluated for efficacy, for example, measurements of cytokine inhibition constants, K_(i), and IC₅₀ values can be obtained by any method chosen by the formulator.

Non-limiting examples of suitable assays include:

-   -   i) UV-visible substrate enzyme assay as described by L. Al         Reiter, Int. J. Peptide Protein Res., 43, 87-96 (1994).     -   ii) Fluorescent substrate enzyme assay as described by         Thornberry et al., Nature, 356, 768-774 (1992).     -   iii) PBMC Cell assay as described in U.S. Pat. No. 6,204,261 B1         Batchelor et al., issued Mar. 20, 2001.         Each of the above citations is included herein by reference.

In addition, Tumor Necrosis Factor, TNF-α, inhibition can be measured by utilizing lipopolysaccharide (LPS) stimulated human monocytic cells (THP-1) as described in:

-   -   i) K. M. Mohler et al., “Protection Against a Lethal Dose of         Endotoxin by an Inhibitor of Tumour Necrosis Factor Processing”,         Nature, 370, pp 218-220 (1994).     -   ii) U.S. Pat. No. 6,297,381 B1 Cirillo et al., issued Oct. 2,         2001, incorporated by reference and reproduced herein below in         relevant portion thereof.

The inhibition of cytokine production can be observed by measuring inhibition of TNF-α in lipopolysaccharide stimulated THP cells. All cells and reagents are diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/mL each) and fetal bovine serum (FBS 3%) (GIBCO, all conc. Final). Assay is performed under sterile conditions, only test compound preparation is non-sterile. Initial stock solutions are made in DMSO followed by dilution into RPMI 1640 2-fold higher than the desired final assay concentration. Confluent THP.1 cells (2×10⁶ cells/mL, final conc.; American Type Culture Company, Rockville, Md.) are added to 96 well polypropylene round bottomed culture plates (Costar 3790; sterile) containing 125 μL test compound (2-fold concentrated) or DMSO vehicle (controls, blanks). DMSO concentration should not exceed 0.2% final. Cell mixture is allowed to preincubate for 30 minutes at 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS, 1 μg/mL final; Sigma L-2630, from E. coli serotype 0111.B4; stored as 1 mg/mL stock in endotoxin screened diluted H₂O vehicle at −80° C.). Blanks (unstimulated) receive H₂O vehicle; final incubation volume is 250 μL. Incubation (4 hours) proceeds as described above. Assay is to be terminated by centrifuging plates 5 minutes at room temperature, 1600 rpm (4033 g); supernatants are then transferred to clean 96 well plates and stored at −80° C. until analyzed for human TNF-α by a commercially available ELISA kit (Biosource #KHC3015, Camarillo, Calif.). The calculated IC₅₀ value is the concentration of the test compound that caused a 50% decrease in the maximal TNF-α production.

All documents cited in the Detailed Description of the Invention are, are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention. 

1. A compound including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, said compound having the formula:

wherein: R has the formula:

R¹ is hydrogen or substituted or unsubstituted C₆-C₁₀ aryl; R² is substituted or unsubstituted C₆-C₁₀ aryl; L and L¹ are linking units each of which is independently chosen from: i) —NH—; ii) —O—; iii) —SO₂—; iv) —C(O)—; v) —C═NOR⁶; vi) —C(R⁶)₂—; vii) —C[═C(R⁶)₂]—; and viii) —C(OR⁵)₂—; R⁵ is hydrogen, —COR⁶, or two R⁵ units can be taken together with the oxygen atoms to form a cyclic ketal ring comprising 5 or 6 atoms; and R⁶ is methyl, ethyl, or n-propyl.
 2. A composition comprising: a) an effective amount of one or more compounds according to claim 1; and b) one or more pharmaceutically acceptable excipients. 